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Extended liver resection carries the risk of post-surgery liver failure involving thrombospondin-1-mediated aggravation of hepatic epithelial plasticity and function. Mesenchymal stromal cells (MSCs), by interfering with thrombospondin-1 (THBS1), counteract hepatic dysfunction, though the mechanisms involved remain unknown. Herein, two-thirds partial hepatectomy in mice increased hepatic THBS1, downstream transforming growth factor-β3, and perturbation of liver tissue homeostasis. All these events were ameliorated by hepatic transfusion of human bone marrow-derived MSCs. Treatment attenuated platelet and macrophage recruitment to the liver, both major sources of THBS1. By mitigating THBS1, MSCs muted surgery-induced tissue deterioration and dysfunction, and thus supported post-hepatectomy regeneration. After liver surgery, patients displayed increased tissue THBS1, which is associated with functional impairment and may indicate a higher risk of post-surgery complications. Since liver dysfunction involving THBS1 improves with MSC treatment in various animal models, it seems feasible to also modulate THBS1 in humans to impede post-surgery acute liver failure.

This article discusses a randomized controlled study that aimed to assess the efficacy and safety of autologous cell suspension transplantation (CST) in patients with non-segmental vitiligo. The study included 17 patients who had been receiving narrowband-UVB and topical treatment for at least 6 months. After 3 and 6 months, the repigmentation rates of the treated and control areas were evaluated. The results showed that CST did not significantly improve repigmentation compared to the control areas. The study suggests that stability of vitiligo without therapy may be necessary for successful CST and that new immunosuppressants or treatment on different body locations may be required for successful repigmentation. [Extracted from the article]

Severe spinal cord injuries (SCIs) usually result in the temporary or permanent impairment of strength, sensation or autonomic functions below the sites of injuries. To date, a large number of therapeutic approaches have been used to ameliorate SCIs, and subsequent stem cell transplantation appears to be a promising strategy. The aim of this study was to evaluate the therapeutic effect of stem cells by changes in the evoked potentials at different time points after a transplantation of spermatogonial stem cells (SSCs) to differentiate the source neurons in a rat model with SCIs, as well as through histopathology. A modified Plemel spinal cord lateral compression model was used. The experiment was divided into a blank, a control and a SSC transplantation group. Motor activity scores, sensory evoked potentials (SEPs) and motor evoked potentials (MEPs) were assessed through motor resuscitation as well as histologic evaluation on each experimental group to determine the improvement. Consistent with our results, motor scores and evoked potentials were significantly improved in the SSC transplantation group. In addition, a histologic assessment showed that the transplanted stem cells had a significant restorative effect on the reconstruction of tissue cells. 1 week after the stem cell transplantation, the SSC transplantation group showed improvement in spinal cord functions and spinal cord pathologic injuries. After 2 weeks and beyond, the SSC transplantation group showed significant improvement in spinal cord functions and spinal cord pathology compared to the control group, meanwhile the evoked potentials and motor function of the hind limbs of rats in the SSC transplantation group were significantly improved. Therefore, the therapeutic strategies for spermatogonial stem cells will be an effective program in the study on SCIs, and we suggest the somatosensory evoked potentials as a tool to assess the degree of recovery from SCIs after the transplantation of stem cells.

Cell transplantation using olfactory ensheathing cells (OECs) is a promising approach for nerve repair but there are numerous limitations with their delivery method. Three-dimensional (3D) cell culture systems potentially offer a powerful approach for cell production and delivery options. To further optimise the use of OECs, strategies to promote cell viability and maintain cell behaviours in 3D cultures become important. We previously demonstrated an anti-diabetic drug, liraglutide, could modulate OEC migration and re-model extracellular matrix in two-dimensional (2D) cultures. In the present study, we further investigated its beneficial effects in our 3D culture system using primary OECs. OECs treated with liraglutide at 100 nM showed improved cell viability and had modulated expression of N-cadherin and β1-integrin (two important cell adhesion molecules). When formed into 3D spheroids, the pre-treated OECs generated spheroids with an increased volume and a decreased cell density compared to control spheroids. OECs that subsequently migrated out of the liraglutide pre-treated spheroids had higher capacity for migration with increased duration and length, which was attributed to a reduction in the pauses during the migration. Moreover, OECs that migrated out from liraglutide spheroids had a more bipolar morphology consistent with higher migratory capacity. In summary, liraglutide improved the viability of OECs, modulated cell adhesion molecules, and resulted in stable 3D cell constructs which conferred enhanced migratory capacity on the OECs. Overall, liraglutide may potentially improve the therapeutic use of OECs for neural repair by enhancing the generation of stable 3D constructs and increasing the migratory behaviour of OECs.

Atrioventricular conduction cardiomyocytes (AVCCs) regulate the rate and rhythm of heart contractions. Dysfunction due to aging or disease can cause atrioventricular (AV) block, interrupting electrical impulses from the atria to the ventricles. Generation of functional atrioventricular conduction like cardiomyocytes (AVCLCs) from human pluripotent stem cells (hPSCs) provides a promising approach to repair damaged atrioventricular conduction tissue by cell transplantation. In this study, we put forward the generation of AVCLCs from hPSCs by stage-specific manipulation of the retinoic acid (RA), WNT, and bone morphogenetic protein (BMP) signaling pathways. These cells express AVCC-specific markers, including the transcription factors TBX3 , MSX2 and NKX2.5 , display functional electrophysiological characteristics and present low conduction velocity (0.07 ± 0.02 m/s). Our findings provide new insights into the understanding of the development of the atrioventricular conduction system and propose a strategy for the treatment of severe atrioventricular conduction block by cell transplantation in future. • Provide an efficient generation protocol of AVCLCs from hPSCs. • RA, WNT and BMP signaling pathways coordinately specify AVCLCs from hPSCs. • The gene pattern and electrophysiology of AVCLCs resemble that of AVN and AVR. • Potential therapy for severe AV block by cell transplantation in future. [ABSTRACT FROM AUTHOR]

Objective: To investigate the influences of astragalus polysacharide(APS) on anti-tumor effect and immune function of esophageal carcinoma(EPC) rats through phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signal pathway. Methods: 50 healthy 6-week-old SPF grade SD rats were randomly divided into model group(group M), cisplatin group(group S), APS low dosage group(group APSL), APS middle dosage group(group APSM) and APS high dosage group(group APSH), with 10 rats in each group. EPC model rats were established by transplantation of Eca109 cells, and 3mg/kg cisplatin and 100, 200, 400 mg/kg APS were given to each rat. Tumor volume and tumor mass were detected, tumor growth inhibition rate, thymus index and spleen index were calculated, histomorphology was observed by HE staining, CD3+, CD4+, CD8+T lymphocyte population were detected by flow cytometer, the relative expressions of PI3K and Akt protein were detected by Western blot. Results: After intervention, tumor volume and tumor mass of group S and group APS were all lower than group M(P＜0.05); the tumor volume and tumor mass of group S and group APSH were all lower than group APSM and group APSL(P＜0.05); the tumor growth inhibition rate of each APS group were 45.59%, 32.35% and 17.65%. The thymus index and spleen index of group S were lower than group M(P＜0.05); the thymus index and spleen index of each APS group were all higher than group S(P＜0.05); while group APSH and APSM were higher than group M(P＜0.05). The CD3+, CD4+ and CD4+/CD8+ of each APS group were higher than group S and group M, while the CD8+ was lower(P＜0.05); group APSH, APSM and APSL also had statistical differences(P＜0.05). The relative expressions of PI3K/Akt signal pathway protein of group S and each APS group were lower than group M(P＜0.05); group APSH, APSM and APSL also had statistical differences(P＜0.05). Conclusion: APS exerts inhibition effect on EPC via regulation of PI3K/Akt signal pathway and immune function, which can provide new thought and theoretical basis for clinical treatment of EPC. [ABSTRACT FROM AUTHOR]

Background: Peripheral artery disease is an ischemic vascular disease caused by the blockage of blood vessels supplying blood to the lower extremities. Mesenchymal stem cells (MSCs) and endothelial colony-forming cells (ECFCs) have been reported to alleviate peripheral artery disease by forming new blood vessels. However, the clinical application of MSCs and ECFCs has been impeded by their poor in vivo engraftment after cell transplantation. To augment in vivo engraftment of transplanted MSCs and ECFCs, we investigated the effects of hybrid cell spheroids, which mimic a tissue-like environment, on the therapeutic efficacy and survival of transplanted cells. Methods: The in vivo survival and angiogenic activities of the spheroids or cell suspension composed of MSCs and ECFCs were measured in a murine hindlimb ischemia model and Matrigel plug assay. In the hindlimb ischemia model, the hybrid spheroids showed enhanced therapeutic effects compared with the control groups, such as adherent cultured cells or spheroids containing either MSCs or ECFCs. Results: Spheroids from MSCs, but not from ECFCs, exhibited prolonged in vivo survival compared with adherent cultured cells, whereas hybrid spheroids composed of MSCs and ECFCs substantially increased the survival of ECFCs. Moreover, single spheroids of either MSCs or ECFCs secreted greater levels of pro-angiogenic factors than adherent cultured cells, and the hybrid spheroids of MSCs and ECFCs promoted the secretion of several pro-angiogenic factors, such as angiopoietin-2 and platelet-derived growth factor. Conclusion: These results suggest that hybrid spheroids containing MSCs can serve as carriers for cell transplantation of ECFCs which have poor in vivo engraftment efficiency. [ABSTRACT FROM AUTHOR]

Purified Retinal Ganglion Cells (RGCs) for in vitro study have been a valuable tool in the study of neural regeneration and in the development of therapies to treat glaucoma. Traditionally, RGCs have been isolated from early postnatal rats and mice, and more recently from human in vitro derived retinal organoids using a two-step immunopanning technique based upon the expression of Thy-1. This technique, however, limits the time periods from which RGCs can be isolated, missing the earliest born RGCs at which time the greatest stage of axon growth occurs, as well as being limited in its use with models of retinal degeneration as Thy-1 is downregulated following injury. While fluorescence associated cell sorting (FACS) in combination with new optogenetically labeled RGCs would be able to overcome this limitation, the use of traditional FACS sorters has been limited to genomic and proteomic studies, as RGCs have little to no survival post-sorting. Here we describe a new method for RGC isolation utilizing a combined immunopanning-fluorescence associated cell sorting (IP-FACS) protocol that initially depletes macrophages and photoreceptors, using immunopanning to enrich for RGCs before using low-pressure FACS to isolate these cells. We demonstrate that RGCs isolated via IP-FACS when compared to RGCs isolated via immunopanning at the same age have similar purity as measured by antibody staining and qRT-PCR; survival as measured by live dead staining; neurite outgrowth; and electrophysiological properties as measured by calcium release response to glutamate. Finally, we demonstrate the ability to isolate RGCs from early embryonic mice prior to the expression of Thy-1 using Brn3b-eGFP optogenetically labeled cells. This method provides a new approach for the isolation of RGCs for the study of early developed RGCs, the study of RGC subtypes and the isolation of RGCs for cell transplantation studies. [ABSTRACT FROM AUTHOR]

The induced pluripotent stem cells (iPSCs) are able to differentiate into dopaminergic neurons and execute the therapeutic effects for Parkinson's disease (PD). Here, we established a animal model of PD in Lanyu pigs by injecting 5 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP). Next, the porcine iPSC-like cells (piPSC-like cells) were differentiated into D18 neuronal progenitors (D18 NPs) that were transplanted into the striatum to evaluate their therapeutic effects of PD. We showed that after 8 weeks of cell transplantation, the behavior score was significantly ameliorated and fully recovered at the 14th week of cell transplantation. The number of dopaminergic neurons was also significantly improved at the end of the experiment although the number was still about 50% lower than that in the control group. Our findings suggest that piPSC-like cell-derived D18 NPs exhibit a potential for the treatment of PD in the Lanyu pig model. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen responsible for the coronavirus disease 2019 (COVID-19) outbreaks that resulted in a catastrophic threat to global health, with more than 500 million cases detected and 5.5 million deaths worldwide. Patients with a COVID-19 infection presented with clinical manifestations ranging from asymptomatic to severe symptoms, resulting in acute lung injury, acute respiratory distress syndrome, and even death. Immune dysregulation through delayed innate immune response or impairment of the adaptive immune response is the key contributor to the pathophysiology of COVID-19 and SARS-CoV-2-induced cytokine storm. Symptomatic and supportive therapy is the fundamental strategy in treating COVID-19 infection, including antivirals, steroid-based therapies, and cell-based immunotherapies. Various studies reported substantial effects of immune-based therapies for patients with COVID-19 to modulate the over-activated immune system while simultaneously refining the body's ability to destroy the virus. However, challenges may arise from the complexity of the disease through the genetic variance of the virus itself and patient heterogeneity, causing increased transmissibility and heightened immune system evasion that rapidly change the intervention and prevention measures for SARS-CoV-2. Cell-based therapy, utilizing stem cells, dendritic cells, natural killer cells, and T cells, among others, are being extensively explored as other potential immunological approaches for preventing and treating SARS-CoV-2-affected patients the similar process was effectively proven in SARS-CoV-1 and MERS-CoV infections. This review provides detailed insights into the innate and adaptive immune response-mediated cell-based immunotherapies in COVID-19 patients. The immune response linking towards engineered autologous or allogenic immune cells for either treatment or preventive therapies is subsequently highlighted in an individual study or in combination with several existing treatments. Up-to-date data on completed and ongoing clinical trials of cell-based agents for preventing or treating COVID-19 are also outlined to provide a guide that can help in treatment decisions and future trials. [ABSTRACT FROM AUTHOR]

Pluripotent stem cell therapy exhibits self-renewal capacity and multi-directional differentiation potential and is considered an important regenerative approach for the treatment of several diseases. However, insufficient cell transplantation efficiency, uncontrollable differentiation, low cell viability, and difficult tracing limit its clinical applications and treatment outcome. Ultrasound (US) has mechanical, cavitation, and thermal effects that can produce different biological effects on organs, tissues, and cells. US can be combined with different US-responsive particles for enhanced physical-chemical stimulation and drug delivery. In the meantime, US also can provide a noninvasive and harmless imaging modality for deep tissue in vivo. An in-depth evaluation of the role and mechanism of action of US in stem cell therapy would enhance understanding of US and encourage research in this field. In this article, we comprehensively review progress in the application of US alone and combined with US-responsive particles for the promotion of proliferation, differentiation, migration, and in vivo detection of stem cells and the potential clinical applications. [ABSTRACT FROM AUTHOR]

Background: Islet cell transplantation is an emerging therapy in the treatment of diabetes mellitus. Differentiation of islet cells from mesenchymal stem cells (MSCs) is a potential solution to the challenge of insufficient donor sources. This study investigated whether human umbilical cord‐derived MSCs could effectively differentiate into insulin‐producing cells (IPCs) and evaluated the therapeutic efficacy of IPCs in treating diabetes. Methods: IPCs were induced from MSCs by a two‐step protocol. IPC expression products were evaluated by western blot and real‐time PCR. IPC insulin secretion was evaluated by ELISA. The viability of IPCs was measured by FDA/PI and dithizone staining. The non‐human primate tree shrew was used as a diabetes model. After a single STZ induction into a diabetes model, a single intraportal transplantation of IPCs, MSCs, or normal saline was performed (n = 6 per group). Blood glucose was monitored for 3 weeks, then the animals were euthanized and the distribution of IPCs in the liver was examined pathologically. Results: After about 3 weeks of in vitro induction, IPCs formed microspheres of 100–200 μm, with >95% viable cells that were dithizone stain positive. IPCs expressed islet‐related genes and proteins and secreted high levels of insulin whether stimulated by low or high levels of glucose. After transplantation of IPCs into diabetic tree shrews, blood glucose levels decreased rapidly to near normal and were significantly lower than the MSC or saline groups for 3 weeks thereafter. Conclusion: We present the novel discovery that IPCs derived from human umbilical cord MSCs exert a therapeutic effect in a non‐human primate model of diabetes. This study provides a preliminary experimental basis for the use of autologous MSC‐derived IPCs in the treatment of human diabetes. [ABSTRACT FROM AUTHOR]

Purpose: The need for chronic systemic immunosuppression, which presents a host of acute risks to transplantation patients, remains the primary limitation for the translation of many cell therapies, such as insulin secreting cells for the treatment of type 1 diabetes. Trophoblasts are the professional tolerogenic cells of the placenta, and they secrete a range of soluble factors to induce antigen specific tolerance toward allogeneic fetal tissue during pregnancy, including extracellular vesicles. Here we develop a trophoblast extracellular vesicle-delivering hydrogel designed for sustained, localized tolerogenic factor delivery within a transplant site to induce localized tolerance toward cell grafts. Methods: We engineer a synthetic poly(ethylene glycol)-based hydrogel system to tether extracellular vesicles for sustained delivery, and compare this system to passive vesicle entrapment within an alginate hydrogel system. We characterize trophoblast extracellular vesicles for size and morphology, and evaluate vesicle tolerogenic protein content via proteomic analysis. We validate the retention and tethering of extracellular vesicles within the hydrogel systems via scanning electron and stimulated emission depletion microscopy, and measure vesicle release rate over time. Finally, we evaluate trophoblast extracellular vesicle influence on natural killer cell activation in vitro. Results: We isolated trophoblast extracellular vesicles and proteomics confirmed the presence of tolerogenic factors. We confirmed the presence of extracellular vesicles within hydrogel delivery vehicles, and synthetic hydrogels extended extracellular vesicle release relative to a passive hydrogel system. Finally, extracellular vesicles reduced natural killer cell activation in vitro, confirming the tolerogenic potential of hydrogel-delivered extracellular vesicles. Conclusions: This tolerogenic extracellular vesicle-delivering hydrogel platform designed for delivery within a transplant site could serve as an alternative to systemic immunosuppression in cell transplantation, potentially reducing the risks associated with cell therapies and widening the eligible patient population. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cells have been shown to survive, re-innervate the striatum, and relieve motor function for up to 2 years in nonhuman primates. CRISPR-Cas9-guided gene editing targeting diabetes-related genes resulted in restored β cell function and diabetes reversal in preclinical models. Autologous hematopoietic stem cell transplantation provides a possible cure for sickle cell disease and β-thalassemia. Successful clinical trials led to six FDA-approved chimeric antigen receptor-modified T cell therapies. Alum-tethered IL-12 demonstrated >400-fold greater retention in the local microenvironment for up to 6 days compared with a non-tethered cytokine counterpart. Programmed cell death 1 (PD-1) ligand chimeric with core streptavidin-presenting microgels led to an increase in the expression of genes encoding regulatory factors such as FoxP3, Ccr4, and PD-1, promoting a tolerogenic microenvironment, and allowed long-term allogeneic graft survival. Localized immunomodulation technologies are rapidly emerging as a new modality with the potential to revolutionize transplantation of cells and organs. In the past decade, cell-based immunomodulation therapies saw clinical success in the treatment of cancer and autoimmune diseases. In this review, we describe recent advances in engineering solutions for the development of localized immunomodulation techniques focusing on cellular and organoid transplantation. We begin by describing cell transplantation and highlighting notable clinical successes, particularly in the areas of stem cell therapy, chimeric antigen receptor (CAR)-T cell therapy, and islet transplantation. Next, we detail recent preclinical studies centered on genome editing and biomaterials to enhance localized immunomodulation. We close by discussing future opportunities to improve clinical and commercial success using these approaches to facilitate long-term immunomodulation technologies. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is an incurable inherited brain disorder characterised by massive degeneration of striatal neurons, which correlates with abnormal accumulation of misfolded mutant huntingtin (mHTT) protein. Research on HD has been hampered by the inability to study early dysfunction and progressive degeneration of human striatal neurons in vivo. To investigate human pathogenesis in a physiologically relevant context, we transplanted human pluripotent stem cell-derived neural progenitor cells (hNPCs) from control and HD patients into the striatum of new-born mice. Most hNPCs differentiated into striatal neurons that projected to their target areas and established synaptic connexions within the host basal ganglia circuitry. Remarkably, HD human striatal neurons first developed soluble forms of mHTT, which primarily targeted endoplasmic reticulum, mitochondria and nuclear membrane to cause structural alterations. Furthermore, HD human cells secreted extracellular vesicles containing mHTT monomers and oligomers, which were internalised by non-mutated mouse striatal neurons triggering cell death. We conclude that interaction of mHTT soluble forms with key cellular organelles initially drives disease progression in HD patients and their transmission through exosomes contributes to spread the disease in a non-cell autonomous manner. [ABSTRACT FROM AUTHOR]

Thanks to their immunomodulatory, tissue-protective and regenerative properties, mesenchymal stromal cells (MSCs) are a promising approach for amyotrophic lateral sclerosis (ALS); however, trials are limited and few follow-up studies have been published. This post-hoc analysis aims to describe the potential long-term effects of MSCs in ALS, analyzing data from two phase 1 clinical trials in ALS patients conducted by our group in 2002 and 2006. We conducted two consecutive phase 1 prospective, open, pilot clinical trials, enrolling a total of 19 ALS patients. We followed patients for the duration of the disease. For each patient, we used the European Network to Cure ALS (ENCALS) survival prediction model to retrospectively calculate the expected survival at diagnosis. We then compared the predicted disease duration with the observed survival, analyzing patients at a single-patient level. Using the ENCALS model, we predicted short survival in one patient, intermediate survival in three patients, long survival in three patients and very long survival in 12 patients. The difference between predicted and observed survival for the whole group was significant and demonstrated a mean predicted survival of 70.79 months (standard deviation [SD], 27.53) and a mean observed survival of 118.8 months (SD, 89.26) (P = 0.016). Based on the monthly ALS Functional Rating Scale–Revised progression rate (median, 0.64/month), we considered 10 of 19 patients slow progressors and nine of 19 patients fast progressors. Of the slow progressors, eight of 10 (80%) had significantly increased disease duration compared with predicted, and only two (20%) had decreased estimated disease duration. By contrast, five of nine (55%) fast progressors had increased disease duration, whereas four (45%) had decreased disease duration. To date, four patients are still alive. The current study represents the first very long-term analysis of survival as an effect of MSC focal transplantation in the central nervous system of ALS patients, demonstrating that MSC transplantation could potentially slow down ALS progression and improve survival. Due to the interindividual variability in clinical course, at the current state of our knowledge, we cannot generalize the results, but these data provide new insights for planning the next generation of efficacy MSC clinical trials in ALS. [ABSTRACT FROM AUTHOR]

Introduction: Measles, mumps, rubella, and even poliomyelitis outbreaks have recently perplexed infectious disease clinicians and epidemiologists globally due to the decline in vaccination coverage rates in children and adults. Measles and yellow fever (YF) have represented an increasing burden on the Brazilian public health system in recent decades. Both diseases are preventable by live‐attenuated viral vaccines (LAVV), which have restricted use in hematopoietic cell transplant (HCT) recipients. Methods: Autologous and allogeneic HCT recipients returning for regular appointments at the outpatient clinic were invited to participate in the study. Patients transplanted for at least 2 years and with a printed copy of the vaccination record were included. Results: We assessed the vaccination records of 273 HCT recipients after the second year of HCT (193 allogeneic and 80 autologous) and observed lower compliance with the YF vaccine (58 patients, 21.2%) than with the measles vaccine (138 patients, 50.5%, p ≤.0001). This is the largest published series of YF vaccination in HCT recipients so far. No severe adverse events occurred. Although expected, chronic graft‐versus‐host disease (GVHD) did not affect the compliance with measles (p =.08) or YF vaccination (p =.7). Indeed, more allogeneic recipients received measles vaccine in comparison with autologous patients (p <.0001), suggesting that chronic GVHD was not the main reason for not being vaccinated. Children and allogeneic HCT were more likely to receive measles vaccine. Time elapsed from HCT >5 years favored both measles and YF vaccination. Conclusion: A better understanding of the reasons for low compliance with LAVV is necessary to overcome this problem. [ABSTRACT FROM AUTHOR]

Background: Osteonecrosis of the femoral head (ONFH) is a disabling disease that can ultimately progress to collapse of the femoral head, often resulting in THA. Core decompression of the femoral head combined with cell therapies have shown beneficial effects in previous clinical studies in patients with early-stage (Association Research Circulation Osseous [ARCO] Stage I and II) ONFH. However, high-quality evidence confirming the efficacy of this treatment modality is still lacking. Questions/purposes: (1) Is core decompression combined with autologous osteoblastic cell transplantation superior to core decompression with placebo implantation in relieving disease-associated pain and preventing radiologic ONFH progression in patients with nontraumatic early-stage ONFH? (2) What adverse events occurred in the treatment and control groups? Methods: This study was a Phase III, multicenter, randomized, double-blind, controlled study conducted from 2011 to 2019 (ClinicalTrails.gov registry number: NCT01529008). Adult patients with ARCO Stage I and II ONFH were randomized (1:1) to receive either core decompression with osteoblastic cell transplantation (5 mL with 20 x 106 cells/mL in the study group) or core decompression with placebo (5 mL of solution without cells in the control group) implantation. Thirty percent (68 of 230) of the screened patients were eligible for inclusion in the study; of these, 94% (64 of 68) underwent a bone marrow harvest or sham procedure (extended safety set) and 79% (54 of 68) were treated (study group: 25 patients; control group: 29). Forty-nine patients were included in the efficacy analyses. Similar proportions of patients in each group completed the study at 24 months of follow-up (study group: 44% [11 of 25]; control: 41% [12 of 29]). The study and control groups were comparable in important ways; for example, in the study and control groups, most patients were men (79% [27 of 34] and 87% [26 of 30], respectively) and had ARCO Stage II ONFH (76% [19 of 25] and 83% [24 of 29], respectively); the mean age was 46 and 45 years in the study and control groups, respectively. The follow-up period was 24 months post-treatment. The primary efficacy endpoint was the composite treatment response at 24 months, comprising the clinical response (clinically important improvement in pain from baseline using the WOMAC VA3.1 pain subscale, defined as 10 mm on a 100-mm scale) and radiologic response (the absence of progression to fracture stage [≥ ARCO Stage III], as assessed by conventional radiography and MRI of the hips). Secondary efficacy endpoints included the percentages of patients achieving a composite treatment response, clinical response, and radiologic response at 12 months, and the percentage of patients undergoing THA at 24 months. We maintained a continuous reporting system for adverse events and serious adverse events related to the study treatment, bone marrow aspiration and sham procedure, or other study procedures throughout the study. A planned, unblinded interim analysis of efficacy and adverse events was completed at 12 months. The study was discontinued because our data safety monitoring board recommended terminating the study for futility based on preselected futility stopping rules: conditional power below 0.20 and p = 0.01 to detect an effect size of 10 mm on the 100-mm WOMAC VA3.1 pain subscale (improvement in pain) and the absence of progression to fracture (≥ ARCO Stage III) observed on radiologic assessment, reflecting the unlikelihood that statistically beneficial results would be reached at 24 months after the treatment. Results: There was no difference between the study and control groups in the proportion of patients who achieved a composite treatment response at 24 months (61% [14 of 23] versus 69% [18 of 26]; p = 0.54). There was no difference in the proportion of patients with a treatment response at 12 months between the study and control groups (14 of 21 versus 15 of 23; p = 0.92), clinical response (17 of 21 versus 16 of 23; p = 0.38), and radiologic response (16 of 21 versus 18 of 23; p = 0.87). With the numbers available, at 24 months, there was no difference in the proportion of patients who underwent THA between the study and control groups (24% [six of 25] versus 14% [four of 29]). There were no serious adverse events related to the study treatment, and only one serious adverse event (procedural pain in the study group) was related to bone marrow aspiration. Nonserious adverse events related to the treatment were rare in the study and control groups (4% [one of 25] versus 14% [four of 29]). Nonserious adverse events related to bone marrow or sham aspiration were reported by 15% (five of 34) of patients in the study group and 7% (two of 30) of patients in the control group. Conclusion: Our study did not show any advantage of autologous osteoblastic cells to improve the results of core decompression in early-stage (precollapse) ONFH. Adverse events related to treatment were rare and generally mild in both groups, although there might have been a potential risk associated with cell expansion. Based on our findings, we do not recommend the combination of osteoblastic cells and core decompression in patients with early-stage ONFH. Further, well-designed studies should be conducted to explore whether other treatment modalities involving a biological approach could improve the overall results of core decompression. Level of Evidence: Level II, therapeutic study. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is an invasive hematopoietic malignancy caused by excessive proliferation of myeloblasts. Classical chemotherapies and cell transplantation therapies have remarkable efficacy in AML treatment; however, 30–40% of patients relapsed or had refractory disease. The resistance of AML is closely related to its inherent cytogenetics or various gene mutations. Recently, phytonanomedicine are found to be effective against resistant AML cells and have become a research focus for nanotechnology development to improve their properties, such as increasing solubility, improving absorption, enhancing bioavailability, and maintaining sustained release and targeting. These novel phytonanomedicine and mineral nanomedicine, including nanocrystals, nanoemulsion, nanoparticles, nanoliposome, and nanomicelles, offer many advantages, such as flexible dosages or forms, multiple routes of administration, and curative effects. Therefore, we reviewed the application and progress of phytomedicine in AML treatment and discussed the limitations and future prospects. This review may provide a solid reference to guide future research on AML treatment. [ABSTRACT FROM AUTHOR]

Background: Parkinson’s disease (PD) is a progressive neurodegenerative condition that primarily affects motor functions; it is caused by the loss of midbrain dopaminergic (mDA) neurons. The therapeutic effects of transplanting humaninduced pluripotent stem cell (iPSC)-derived mDA neural progenitor cells in animal PD models are known and are being evaluated in an ongoing clinical trial. However, However, improvements in the safety and efficiency of differentiation-inducing methods are crucial for providing a larger scale of cell therapy studies. This study aimed to investigate the usefulness of dopaminergic progenitor cells derived from human iPSCs by our previously reported method, which promotes differentiation and neuronal maturation by treating iPSCs with three inhibitors at the start of induction. Methods: Healthy subject-derived iPS cells were induced into mDA progenitor cells by the CTraS-mediated method we previously reported, and their proprieties and dopaminergic differentiation efficiency were examined in vitro. Then, the induced mDA progenitors were transplanted into 6-hydroxydopamine-lesioned PD model mice, and their efficacy in improving motor function, cell viability, and differentiation ability in vivo was evaluated for 16 weeks. Results: Approximately ≥80% of cells induced by this method without sorting expressed mDA progenitor markers and differentiated primarily into A9 dopaminergic neurons in vitro. After transplantation in 6-hydroxydopamine-lesioned PD model mice, more than 90% of the engrafted cells differentiated into the lineage of mDA neurons, and approximately 15% developed into mature mDA neurons without tumour formation. The grafted PD model mice also demonstrated significantly improved motor functions. Conclusion: This study suggests that the differentiation protocol for the preparation of mDA progenitors is a promising option for cell therapy in patients with PD. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) starts with a mechanical and/or bio-chemical insult, followed by a secondary phase, leading progressively to severe collapse of the nerve tissue. Compared to the peripheral nervous system, injured spinal cord is characterized by weak axonal regeneration, which leaves most patients impaired or paralyzed throughout lifetime. Therefore, confining, alleviating, or reducing the expansion of secondary injuries and promoting functional connections between rostral and caudal regions of lesion are the main goals of SCI therapy. Interleukin 10 (IL-10), as a pivotal anti-inflammatory and immunomodulatory cytokine, exerts a wide spectrum of positive effects in the treatment of SCI. The mechanisms underlying therapeutic effects mainly include anti-oxidative stress, limiting excessive inflammation, anti-apoptosis, antinociceptive effects, etc. Furthermore, IL-10 displays synergistic effects when combined with cell transplantation or neurotrophic factor, enhancing treatment outcomes. This review lists pleiotropic mechanisms underlying IL-10-mediated neuroprotection after SCI, which may offer fresh perspectives for clinical translation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preliminary studies of the research team have shown that bone marrow mesenchymal stem cells can reduce pulmonary inflammation and pulmonary fibrosis in rats caused by silica dust, and no obvious rejection or side effects were found. However so far, almost all reports on the treatment of silicosis animals with bone marrow mesenchymal stem cells are single infusion, and there is no report comparing the effect of multiple repeated infusions and single infusions. OBJECTIVE: To investigate the effect of frequency of bone marrow mesenchymal stem cell infusion on pulmonary fibrosis in rats exposed to silica dust. METHODS: SD rats were randomly divided into normal control group, model group, single infusion group, and multiple infusion group, with 6 rats in each group. Rats in the latter three groups were treated with 1 mL SiO2 suspension at a concentration of 30 mg/mL by tracheal injection, and rats in normal control group were treated with equal volume of normal saline. The single infusion group was injected with 5×109 L-1 0.5 mL bone marrow mesenchymal stem cell suspension via caudal vein on day 28 after dust exposure; the multiple infusion group was injected with bone marrow mesenchymal stem cell suspension on day 28, 35 and 42 after dust exposure; the model group and the normal control group were injected with equal volume of normal saline. After 84 days of experiment, lung CT scan was performed to weigh and calculate lung coefficient in each group. Hematoxylin-eosin staining and Masson staining were performed to detect the levels of hydroxyproline in lung tissue and transforming growth factor β1 in serum. RESULTS AND CONCLUSION: (1) Lung CT images showed that no abnormality was detected in rat lungs of the normal control group. In model group, small granular high-density shadows with diffused distribution and different sizes were observed in both lungs, as well as reticular fiber shadow or cable shadow. The density of the granular shadow distribution and the fiberoptic area were all decreased in the rat lung field of the single-infusion and multiple-infusion groups. (2) Hematoxylin-eosin staining showed that diffuse silicon nodules were seen in the model group, which were fused into films in a large area and infiltrated by lymphocytes. In the single infusion group, there were silicon nodules, local fusion, fibrous tissue hyperplasia, and lymphocyte infiltration in alveolar septum. In the multiple infusion group, a small number of silicon nodules, interstitial fibrous hyperplasia and lymphocyte infiltration were observed. (3) Masson staining showed that in the model group, massive collagen proliferation was seen; small collagen fiber was found in the widened alveolar interval and bronchus and vessels the in multiple infusion group; collagen fibers in single infusion group were between model group and multiple infusion group. (4) Hydroxyproline content in lung tissue, lung collagen volume fraction and serum transforming growth factor β1 level from low to high were normal control, multiple infusion, single infusion, and model groups. Lung hydroxyproline content and collagen volume fraction varied significantly between the groups (P < 0.05). There was significant difference in transforming growth factor β1 level between all the other groups (P < 0.05) except for the model group and the single infusion group as well as single and multiple infusion groups (P > 0.05). (5) Results indicate that multiple infusion of bone marrow mesenchymal stem cells is more effective than single infusion on pulmonary fibrosis induced by silica dust. [ABSTRACT FROM AUTHOR]

Severe combined immunodeficiency (SCID) is fatal unless durable adaptive immunity is established, most commonly through allogeneic haematopoietic cell transplantation (HCT). The Primary Immune Deficiency Treatment Consortium (PIDTC) explored factors affecting the survival of individuals with SCID over almost four decades, focusing on the effects of population-based newborn screening for SCID that was initiated in 2008 and expanded during 2010–18. We analysed transplantation-related data from children with SCID treated at 34 PIDTC sites in the USA and Canada, using the calendar time intervals 1982–89, 1990–99, 2000–09, and 2010–18. Categorical variables were compared by χ2 test and continuous outcomes by the Kruskal-Wallis test. Overall survival was estimated by the Kaplan-Meier method. A multivariable analysis using Cox proportional hazards regression models examined risk factors for HCT outcomes, including the variables of time interval of HCT, infection status and age at HCT, trigger for diagnosis, SCID type and genotype, race and ethnicity of the patient, non-HLA-matched sibling donor type, graft type, GVHD prophylaxis, and conditioning intensity. For 902 children with confirmed SCID, 5-year overall survival remained unchanged at 72%–73% for 28 years until 2010–18, when it increased to 87% (95% CI 82·1–90·6; n=268; p=0·0005). For children identified as having SCID by newborn screening since 2010, 5-year overall survival was 92·5% (95% CI 85·8–96·1), better than that of children identified by clinical illness or family history in the same interval (79·9% [69·5–87·0] and 85·4% [71·8–92·8], respectively [p=0·043]). Multivariable analysis demonstrated that the factors of active infection (hazard ratio [HR] 2·41, 95% CI 1·56–3·72; p<0·0001), age 3·5 months or older at HCT (2·12, 1·38–3·24; p=0·001), Black or African-American race (2·33, 1·56–3·46; p<0·0001), and certain SCID genotypes to be associated with lower overall survival during all time intervals. Moreover, after adjusting for several factors in this multivariable analysis, HCT after 2010 no longer conveyed a survival advantage over earlier time intervals studied (HR 0·73, 95% CI 0·43–1·26; p=0·097). This indicated that younger age and freedom from infections at HCT, both directly driven by newborn screening, were the main drivers for recent improvement in overall survival. Population-based newborn screening has facilitated the identification of infants with SCID early in life, in turn leading to prompt HCT while avoiding infections. Public health programmes worldwide can benefit from this definitive demonstration of the value of newborn screening for SCID. National Institute of Allergy and Infectious Diseases, Office of Rare Diseases Research, and National Center for Advancing Translational Sciences. [ABSTRACT FROM AUTHOR]

While progress has been made in the development of islet cell transplantation (ICT) as a viable alternative to the use of exogenous insulin therapy in the treatment of type 1 diabetes, it has not yet achieved its full potential in clinical studies. Ideally, ICT would enable lifelong maintenance of euglycemia without the need for exogenous insulin, blood glucose monitoring or systemic immune suppression. To achieve such an optimal result, therapeutic approaches should simultaneously promote long‐term islet viability, functionality, and localized immune protection. In practice, however, these factors are typically tackled individually. Furthermore, while the requirements of optimal ICT are implicitly acknowledged across numerous publications, the literature contains few comprehensive articulations of the target product profile (TPP) for an optimal ICT product, including key characteristics of safety and efficacy. This review aims to provide a novel TPP for ICT and presents promising tried and untried combinatorial approaches that could be used to achieve the target product profile. We also highlight regulatory barriers to the development and adoption of ICT, particularly in the United States, where ICT is only approved for use in academic clinical trials and is not reimbursed by insurance carriers. Overall, this review argues that the clear definition of a TPP in addition to the use of combinatorial approaches could help to overcome the clinical barriers to the widespread adoption of ICT for the treatment of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Summary: Innate lymphoid cells (ILCs) are a family of lymphocytes with essential roles in tissue homeostasis and immunity. Along with other tissue-resident immune populations, distinct subsets of ILCs have important roles in either promoting or inhibiting immune tolerance in a variety of contexts, including cancer and autoimmunity. In solid organ and hematopoietic stem cell transplantation, both donor and recipient-derived ILCs could contribute to immune tolerance or rejection, yet understanding of protective or pathogenic functions are only beginning to emerge. In addition to roles in directing or regulating immune responses, ILCs interface with parenchymal cells to support tissue homeostasis and even regeneration. Whether specific ILCs are tissue-protective or enhance ischemia reperfusion injury or fibrosis is of particular interest to the field of transplantation, beyond any roles in limiting or promoting allograft rejection or graft-versus host disease. Within this review, we discuss the current understanding of ILCs functions in promoting immune tolerance and tissue repair at homeostasis and in the context of transplantation and highlight where targeting or harnessing ILCs could have applications in novel transplant therapies. In this review, Mak and Reid et al. explore protective versus pathogenic functions of innate lymphoid cell (ILCs) family members in transplantation. They further highlight where harnessing or targeting ILCs could be advantageous for transplantation, and discuss challenges limiting clinical translation [ABSTRACT FROM AUTHOR]

Summary: An efficient immunological reconstitution construes the pillar for the success of allogeneic haematopoietic cell transplantation (HCT) in haematological disorders. Factors influencing post‐transplant immune recovery have been largely investigated across multiple cohorts issuing heterogeneous results. Differences in outcomes in adult and paediatric populations suggest an age‐related contribution to post‐transplant immune reconstitution; however, it is unclear how recipient and donor age may affect the dynamics of single immune cells. Here, we retrospectively collected and analysed immunological data of 174 patients (58 children and 116 adults) consecutively transplanted for haematological disorders in our centre. We show that trajectories of specific immune cells were strictly dependent on recipient age and pretransplant virus exposure, with the strongest effect seen on T CD4+ and B‐cell counterparts, while donor age and transplant platforms had a minimal impact. This mirrored different kinetics of immune reconstitution in adult and paediatric patients, with major divergences in immune cell composition in late post‐transplant phases, featuring better survival, relapse‐free survival and cumulative incidence of pathogen‐specific infections in younger patients. Altogether, these findings underpin the importance of recipient age on post‐transplant immune cell recovery and define the basic dynamics of the immune reconstitution in paediatric and adult populations as a benchmark for future studies. [ABSTRACT FROM AUTHOR]

Scaffolding structures made of biocompatible and biodegradable polymers are employed in tissue engineering applications to allow cells to perform the activities required to generate new tissue. However, the morphological, chemical, and thermal compatibility of these surfaces with the target tissue should be investigated before cell transplantation. Polymers like polylactic acid (PLA), poly (L-lactide) (PLLA), and polycaprolactone (PCL), which are synthetic biomaterials with high biocompatibility and adjustable biodegradability, have piqued the interest of tissue engineering researchers for years. In the study, electrospun fibrous surfaces with various ratios of PLA/PCL and PLLA/PCL blends (100/0, 10/90, 20/80, 30/70, 40/60, 50/50, and 0/100) are produced. The morphological, chemical, and thermal properties of the suggested surfaces are examined. Although smooth fiber formation is not detected on some surfaces, fibrous surfaces with fiber diameters of 0.962–1.733 µm and porosities of 19.83–29.54% have been observed. Chemical analyses, on the other hand, reveal no solvent residue on surfaces produced with organic solvent systems, indicating that the harmful effect of solvent systems has been eradicated from the fiber surface. Thermal analyses also provide information regarding the crystallinity of surfaces, which will assist future biodegradability research. According to the thermal analysis, the PLA/PCL and PLLA/PCL blend ratios have a significant impact on the surface crystallinity. [ABSTRACT FROM AUTHOR]

At present, no effective strategy exists to slow down the progression of Alzheimer’s disease (AD). A deeper understanding of the pathogenesis of AD and the development of new therapeutic approaches are essential. Stem cell transplantation for the treatment of neurodegenerative diseases is currently a research hotspot. Numerous studies have suggested that neural stem cells (NSCs) can differentiate into functional neurons, replace dead neurons, and form synaptic connections with adjacent surviving neurons, thereby achieving a therapeutic effect. In theory, the use of NSCs to replace and restore damaged cholinergic neurons and synapses may provide a new therapeutic option for AD. This review summarizes the recent preclinical research progress of NSC transplantation for the treatment of AD. [ABSTRACT FROM AUTHOR]

For cellular or tissue transplantation using induced pluripotent stem cells (iPSCs), from the viewpoint of time and economic cost, the use of allogeneic ones is being considered. Immune regulation is one of the key issues in successful allogeneic transplantation. To reduce the risk of rejection, several attempts have been reported to eliminate effects of the major histocompatibility complex (MHC) on the iPSC-derived grafts. On the other hand, we have shown that minor antigen-induced rejection is not negligible even when the MHC's impact is mitigated. In organ transplantation, it is known that donor-specific transfusion (DST) can specifically control immune responses to the donor. However, whether DST could control the immune response in iPSC-based transplantation was not clarified. In this study, using a mouse skin transplantation model, we demonstrate that infusion of donor splenocytes can promote allograft tolerance in the MHC-matched but minor antigen-mismatched conditions. When narrowing down the cell types, we found that infusion of isolated splenic B cells was sufficient to control rejection. As a mechanism, the administration of donor B cells induced unresponsiveness but not deletion in recipient T cells, suggesting that the tolerance was induced in the periphery. The donor B cell transfusion induced allogeneic iPSC engraftment. These results suggest for the first time a possibility that DST using donor B cells could induce tolerance against allogeneic iPSC-derived grafts. [ABSTRACT FROM AUTHOR]

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has emerged as a curative measure for life-threatening hematological disorders. It can be autologous or allogeneic depending on the disease characteristics. Providing transfusion support to the transplant patients can be challenging, especially in AB-mismatched allogeneic HSCT. In this study, we investigated the impact of ABO incompatibility in patients undergoing allogeneic HSCT. MATERIALS AND METHODS: A retrospective review was conducted in 76 patients with hematological diseases who underwent allogeneic HSCT. Transfusion requirements, engraftment profile, incidence of graft versus host disease (GvHD), and mortality for a period of 1 year were analyzed. RESULTS: ABO incompatibility between donor and the patient did not significantly affect the neutrophil and platelet (PLT) engraftment time (P = 0.389, 0.349, respectively), packed red blood cells transfusion requirement, and duration of initial hospital stay. However, patients of ABO-incompatible HSCT received more PLT transfusions posttransplant which was statistically significant. 29.1% of ABO compatible and 16.7% incompatible HSCT patients developed GVHD. Mortality rates in the two groups were 16.7% and 8.3%, respectively. However, differences in both the parameters were not statistically significant. CONCLUSION: Our study showed that ABO incompatibility does not significantly affect the outcome and should not be a limiting factor for selection of donor. Donor availability and human leukocyte antigen (HLA) matching remain the critical selection criteria. [ABSTRACT FROM AUTHOR]

Simple Summary: Invasive fungal infections (IFD) are a significant cause of morbidity and mortality in patients with hematological malignant disorders. The aim of this retrospective study was to investigate the prevalence and outcome of IFD in patients who received cellular therapies. Adult hematopoietic cell transplantation (HCT), chimeric antigen receptor (CAR) T cell, and gene therapy recipients were retrospectively enrolled. We studied 950 patients who received cellular therapies. No CAR T cell and gene therapy patient showed IFD whereas 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. A total of 11/473 allogeneic HCT recipients developed probable IFD, possible IFD was found in 31/473 and IFD was proven in 10/473. Three patients were reported to have a second episode of IFD. IFDs were associated with poor outcomes in allogeneic HCT recipients. Further studies are needed to improve diagnostics and therapeutics in high-risk populations, such as allogeneic HCT recipients in whom IFD is associated with poor outcomes. (1) Background: Autologous, allogeneic hematopoietic cell transplantation (HCT) and other cellular therapies, including CAR T cell and gene therapy, constitute a cornerstone in the management of various benign and malignant hematological disorders. Invasive fungal infections (IFD) remain a significant cause of morbidity and mortality in HCT recipients. Therefore, we investigated the prevalence and risk factors of IFD following HCT and other cellular therapies in an era of novel antifungal prophylaxis. (2) Methods: In this study, we retrospectively enrolled adult HCT recipients who were treated at our JACIE-accredited center according to standard operating procedures over the last decade (2013–2022). (3) Results: 950 patients who received cellular therapies were studied. None of the 19 CAR T cell and neither of the two gene therapy recipients developed IFD whereas 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. Overall, 11 patients who received allogeneic HCT experienced probable IFD, possible IFD was found in 31/473, and IFD was proven in 10/473. A second IFD episode was present in three patients. Four-year OS was significantly lower in proven compared to probable IFD (p = 0.041) and was independently associated with HCT-CI (p = 0.040) and chronic GVHD (p = 0.045). (4) Conclusions: In this real-world cohort, the prevalence of proven and probable IFD in an era of novel antifungal prophylaxis was found to be relatively low. However, IFDs were associated with poor outcomes for patients who received allogeneic HCT. [ABSTRACT FROM AUTHOR]

The prolonged cooling of cells results in cell death, in which both apoptosis and ferroptosis have been implicated. Preservation solutions such as the University of Wisconsin Cold Storage Solution (UW) encompass approaches addressing both. The use of UW improves survival and thus extends preservation limits, yet it remains unclear how exactly organ preservation solutions exert their cold protection. Thus, we explored cooling effects on lipid peroxidation and adenosine triphosphate (ATP) levels and the actions of blockers of apoptosis and ferroptosis, and of compounds enhancing mitochondrial function. Cooling and rewarming experiments were performed in a cellular transplantation model using Human Embryonic Kidney (HEK) 293 cells. Cell viability was assessed by neutral red assay. Lipid peroxidation levels were measured by Western blot against 4-Hydroxy-Nonenal (4HNE) and the determination of Malondialdehyde (MDA). ATP was measured by luciferase assay. Cooling beyond 5 h in Dulbecco's Modified Eagle Medium (DMEM) induced complete cell death in HEK293, whereas cooling in UW preserved ~60% of the cells, with a gradual decline afterwards. Cooling-induced cell death was not precluded by inhibiting apoptosis. In contrast, the blocking of ferroptosis by Ferrostatin-1 or maintaining of mitochondrial function by the 6-chromanol SUL150 completely inhibited cell death both in DMEM- and UW-cooled cells. Cooling for 24 h in UW followed by rewarming for 15 min induced a ~50% increase in MDA, while concomitantly lowering ATP by >90%. Treatment with SUL150 of cooled and rewarmed HEK293 effectively precluded the increase in MDA and preserved normal ATP in both DMEM- and UW-cooled cells. Likewise, treatment with Ferrostatin-1 blocked the MDA increase and preserved the ATP of rewarmed UW HEK293 cells. Cooling-induced HEK293 cell death from hypothermia and/or rewarming was caused by ferroptosis rather than apoptosis. UW slowed down ferroptosis during hypothermia, but lipid peroxidation and ATP depletion rapidly ensued upon rewarming, ultimately resulting in complete cell death. Treatment throughout UW cooling with small-molecule Ferrostatin-1 or the 6-chromanol SUL150 effectively prevented ferroptosis, maintained ATP, and limited lipid peroxidation in UW-cooled cells. Counteracting ferroptosis during cooling in UW-based preservation solutions may provide a simple method to improve graft survival following cold static cooling. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests the critical role of the gut–brain axis (GBA) in Parkinson's disease (PD) pathology and treatment. Recently, stem cell transplantation in transgenic PD mice further implicated the GBA's contribution to the therapeutic effects of transplanted stem cells. In particular, intravenous transplantation of human umbilical-cord-blood-derived stem/progenitor cells and plasma reduced motor deficits, improved nigral dopaminergic neuronal survival, and dampened α-synuclein and inflammatory-relevant microbiota and cytokines in both the gut and brain of mouse and rat PD models. That the gut robustly responded to intravenously transplanted stem cells and prompted us to examine in the present study whether direct cell implantation into the gut of transgenic PD mice would enhance the therapeutic effects of stem cells. Contrary to our hypothesis, results revealed that intragut transplantation of stem cells exacerbated motor and gut motility deficits that corresponded with the aggravated expression of inflammatory microbiota, cytokines, and α-synuclein in both the gut and brain of transgenic PD mice. These results suggest that, while the GBA stands as a major source of inflammation in PD, targeting the gut directly for stem cell transplantation may not improve, but may even worsen, functional outcomes, likely due to the invasive approach exacerbating the already inflamed gut. The minimally invasive intravenous transplantation, which likely avoided worsening the inflammatory response of the gut, appears to be a more optimal cell delivery route to ameliorate PD symptoms. [ABSTRACT FROM AUTHOR]

Biobanking of pancreatic islets for transplantation could solve the shortage of donors, and cryopreservation of vitrified islets is a possible approach. However, a technological barrier is rewarming of large volumes both uniformly and rapidly to prevent ice formation due to devitrification. Here, we describe successful recovery of islets from the vitrified state using a volumetric rewarming technology called "nanowarming," which is inductive heating of magnetic nanoparticles under an alternating magnetic field. Convective warming using a 37°C water bath as the gold standard for rewarming of vitrified samples resulted in a decrease in the viability of mouse islets in large volumes (>1 ml) owing to devitrification caused by slow warming. Nanowarming showed uniform and rapid rewarming of vitrified islets in large volumes. The viability of nanowarmed islets was significantly improved and islets transplanted into streptozotocin‐induced diabetic mice successfully lowered serum glucose. The results suggest that nanowarming will lead to a breakthrough in biobanking of islets for transplantation. [ABSTRACT FROM AUTHOR]

Cell transplantation therapy using human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NS/PCs) has attracted attention as a regenerative therapy for spinal cord injury (SCI), and its efficacy in treating the subacute phase of SCI has been reported in numerous studies. However, few studies have focused on treatment in the chronic phase, which accounts for many patients, suggesting that there are factors that are difficult to overcome in the treatment of chronic SCI. The search for therapeutic strategies that focus on chronic SCI is fraught with challenges, and the combination of different therapies is thought to be the key to a solution. In addition, many issues remain to be addressed, including the investigation of therapeutic approaches for more severe injury models of chronic SCI and the acquisition of practical motor function. This review summarizes the current progress in regenerative therapy for SCI and discusses the prospects for regenerative medicine, particularly in animal models of chronic SCI. [ABSTRACT FROM AUTHOR]

The adult heart displays poor reparative capacities after injury. Cell transplantation and tissue engineering approaches have emerged as possible therapeutic options. Several stem cell populations have been largely used to treat the infarcted myocardium. Nevertheless, transplanted cells displayed limited ability to establish functional connections with the host cardiomyocytes. In this study, we provide a new experimental tool, named 3D eX vivo muscle engineered tissue (X-MET), to define the contribution of mechanical stimuli in triggering functional remodeling and to rescue cardiac ischemia. We revealed that mechanical stimuli trigger a functional remodeling of the 3D skeletal muscle system toward a cardiac muscle-like structure. This was supported by molecular and functional analyses, demonstrating that remodeled X-MET expresses relevant markers of functional cardiomyocytes, compared to unstimulated and to 2D- skeletal muscle culture system. Interestingly, transplanted remodeled X-MET preserved heart function in a murine model of chronic myocardial ischemia and increased survival of transplanted injured mice. X-MET implantation resulted in repression of pro-inflammatory cytokines, induction of anti-inflammatory cytokines, and reduction in collagen deposition. Altogether, our findings indicate that biomechanical stimulation induced a cardiac functional remodeling of X-MET, which showed promising seminal results as a therapeutic product for the development of novel strategies for regenerative medicine. [ABSTRACT FROM AUTHOR]

Transplantation of stem cell-derived retinal pigment epithelial (RPE) cells is considered a viable therapeutic option for age-related macular degeneration (AMD). Several landmark Phase I/II clinical trials have demonstrated safety and tolerability of RPE transplants in AMD patients, albeit with limited efficacy. Currently, there is limited understanding of how the recipient retina regulates the survival, maturation, and fate specification of transplanted RPE cells. To address this, we transplanted stem cell-derived RPE into the subretinal space of immunocompetent rabbits for 1 mo and conducted single-cell RNA sequencing analyses on the explanted RPE monolayers, compared to their age-matched in vitro counterparts. We observed an unequivocal retention of RPE identity, and a trajectory-inferred survival of all in vitro RPE populations after transplantation. Furthermore, there was a unidirectional maturation toward the native adult human RPE state in all transplanted RPE, regardless of stem cell resource. Gene regulatory network analysis suggests that tripartite transcription factors (FOS, JUND, and MAFF) may be specifically activated in posttransplanted RPE cells, to regulate canonical RPE signature gene expression crucial for supporting host photoreceptor function, and to regulate prosurvival genes required for transplanted RPE's adaptation to the host subretinal microenvironment. These findings shed insights into the transcriptional landscape of RPE cells after subretinal transplantation, with important implications for cell-based therapy for AMD. [ABSTRACT FROM AUTHOR]

Objectives: Bone marrow-derived mesenchymal stem cells (BMSCs) are considered to have potential clinical application value in the treatment of acute lung injury (ALI). Myeloid-derived growth factor (MYDGF) can promote the proliferation of stem cell. We hypothesized that MYDGF may play a role in reducing lung injury in vitro and in vivo through bone marrow mesenchymal stem cells. Methods: An in vitro model of lipopolysaccharide (LPS)(MLE-12) was established, which was divided into five groups: A: MLE-12; B: MLE-12+LPS; C: MLE-12+LPS + BMSCs; D: MLE-12+LPS + MYDGF; and E: MLE-12+LPS + BMSCs + MYDGF. A Cell Counting Kit-8 was used to detect the OD value. And an ALI model was constructed by inducing mice with a lipopolysaccharide. Forty male Balb/c mice were randomly divided into five groups: A control group; B: model group; C: LPS + BMSCs; D: LPS + MYDGF; E: LPS +BMSCs +MYDGF. Specimens were collected after 24 h. Hematoxylin-eosin (HE)-staining was performed on the tissue sections. The protein concentration in the alveolar lavage fluid was measure by bicinchoninic acid (BCA). The NF-κB, p-Akt, Bax, and Bcl-2 protein expression was detected through Western blotting, and Enzyme linked immunosorbent assay (ELISA) was used to measure the expression of serum interleukin-6, interleukin-10, and TNF-α. Results: Compared with the model group, BMSCs and MYDGF can alleviate the ALI induced by lipopolysaccharide in vitro and vivo (p <.05). Conclusion: We found that the combined treatment effect of MYDGF and BMSCs was better than using MYDGF or BMSCs alone. We speculate that a pretreatment with MYDGF after ALI in mice may improve the survival and growth of transplanted MSCs, thereby improving the curative effect of cell transplantation. [ABSTRACT FROM AUTHOR]

This study aimed to identify the benefits of autologous-stem cell transplantation (auto-SCT) and allogeneic-SCT (allo-SCT) in patients with aggressive T-cell lymphomas to aid in the selection of transplantation type in clinical practice. This study retrospectively analyzed data from 598 patients who underwent transplantation for T-cell lymphomas from 2010 to 2020. In total, 317 patients underwent up-front SCT as consolidation therapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 68.7% and 76.1%, respectively. Patients who underwent auto-SCT had significantly better OS (p = 0.026) than those who underwent allo-SCT; however, no statistical difference in PFS was found. Transplantation was used as a salvage therapy in 188 patients who had relapsed/refractory disease. Overall, 96 (51.1%) patients underwent auto-SCT and 92 (48.9%) patients underwent allo-SCT. Auto-SCT improved long-term survival in patients with complete remission (CR). Allo-SCT demonstrated better 3-year PFS in patients with partial remission and relapsed/refractory disease status. However, >50% of patients died within 1 year of allo-SCT. As a consolidative therapy, up-front auto-SCT demonstrated a survival benefit. Auto-SCT was also effective in patients who achieved CR after salvage therapy. If the disease persists or cannot be controlled, allo-SCT may be considered with reduced intensity conditioning. [ABSTRACT FROM AUTHOR]

BACKGROUND: Glioblastoma is a common malignant brain tumor for adults with poor prognosis and remains lack of efficient treatments. OBJECTIVE: To investigate the efficacy of single high-dose radiotherapy on glioblastoma and the feasibility of oligodendrocyte progenitor cells in the repair of radiation-induced brain injury. METHODS: Plasmid transfection was used to develop human U-87 MG cell line expressing luciferase (Luc). Fifteen Fisher 344 rats bearing Luc-U-87 MG glioblastoma were randomly divided into tumor model group (n=3), radiotherapy group (n=6), and oligodendrocyte progenitor cell transplantation group (n=6). Single high-dose radiotherapy (80 Gy) was given in the latter two groups and cell transplantation was performed in the last group 5 weeks after radiotherapy. In vivo imaging was employed to monitor the tumor growth. MRI was performed to observe the cerebral structure changes induced by radiation. Kaplan-Meier analysis was used to determine the effect of cell transplantation on the survival rate of irradiated rats. Survival and differentiation of transplanted cells were histologically observed. RESULTS AND CONCLUSION: In vitro imaging results showed that the transfected U-87 MG cells reacted with the Luc substrate to produce bioluminescence signals. Signal intensity had a positive linear correlation with the number of transfected cells. Intracranial glioblastoma signals in the tumor model rats continued to increase until their death at 5 weeks after tumor inoculation. Two weeks after radiotherapy, the bioluminescence signal started to decline in the radiotherapy group and was not detected at 4 weeks. Necrotic tumor tissue was observed on T2WI at 5 weeks after radiotherapy but not at 10 weeks, at which timepoint the abnormal signal indicative of brain injury appeared. However, there were no similar signals in the cell transplantation group. Fifteen weeks later, T2WI showed hypo- and hyperintensity signals in the brain parenchyma for all the rats which received irradiation, whereas the injury signal in the radiotherapy group was stronger than that in the cell transplantation group. The survival analysis results revealed the median survival time of the tumor model group, radiotherapy group, and cell transplantation group were 30, 114.5, and 232.5 days, respectively. There were significant differences in the median survival time among groups (P < 0.01). Histological findings showed the transplanted cells survived with multipolarity and some of them expressed myelin basic protein. Moreover, the expression of myelin basic protein in the cell transplantation group was significantly higher than that in the radiotherapy group (P < 0.01). All these findings indicate that single high-dose radiotherapy can effective treat human-derived glioblastoma in rats. Oligodendrocyte progenitor cells transplanted are capable of repairing radiation-induced brain injury, thereby prolonging the survival of irradiated rats. Remyelination is one of the mechanisms accounting for brain tissue repair. [ABSTRACT FROM AUTHOR]

Summary: Pre‐transplant measurable residual disease (MRD) predicts relapse and outcome of allogeneic haematopoietic cell transplantation (allo‐HCT). The impact of MRD on the outcomes of post‐transplant cyclophosphamide (PTCy)‐based allo‐HCT from a matched unrelated donor (UD) is unknown. This study assessed the impact of MRD in acute myeloid leukaemia (AML) in the first complete remission (CR1). A total of 272 patients (MRD negative [MRD−], n = 165; MRD positive [MRD+], n = 107) with a median follow‐up of 19 (range: 16–24) months were studied. The incidence of grades II–IV and grades III–IV acute GVHD at day 180 was 25.2% and 25% (p = 0.99), and 10.6% and 6.8% (p = 0.29), respectively, and 2‐year chronic GVHD was 35% and 30.4% (p = 0.96) in MRD+ and MRD− cohorts, respectively. In multivariate analysis, MRD+ status was associated with a higher incidence of relapse (RI) (hazard ratio [HR] = 2.56, 95% CI: 1.39–4.72), lower leukaemia‐free survival (LFS) (HR = 2.04, 95% CI: 1.23–3.39), overall survival (OS) (HR = 1.83, 95% CI: 1.04–3.25) and GVHD‐free, relapse‐free survival (GRFS) (HR = 1.69, 95% CI: 1.10–2.58). MRD status did not have a significant impact on non‐relapse mortality (NRM), or acute or chronic GVHD risk. Among patients with AML undergoing UD allo‐HCT with PTCy, pre‐transplant MRD+ status predicted a higher relapse rate, lower LFS, OS and GRFS. [ABSTRACT FROM AUTHOR]

Summary: Haematopoietic stem cell reinjection may be a curative option for poor graft function after haematopoietic stem cell transplantation; however, literature supporting its use remains limited. We conducted a multicentre retrospective study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, including 55 patients. We demonstrated response rates of nearly 40% and two‐year survival of more than 60% in the context of an otherwise deadly complication and we observed that the timing of injection and the degree of cytopenia are strongly associated with outcomes. This study shows the feasibility of the procedure informing on its epidemiology, outcomes and prognostic factors, setting the stage for future guidelines. [ABSTRACT FROM AUTHOR]

Myocardial remodeling is an inevitable risk factor for cardiac arrhythmias and can potentially be corrected with cell therapy. Although the generation of cardiac cells ex vivo is possible, specific approaches to cell replacement therapy remain unclear. On the one hand, adhesive myocyte cells must be viable and conjugated with the electromechanical syncytium of the recipient tissue, which is unattainable without an external scaffold substrate. On the other hand, the outer scaffold may hinder cell delivery, for example, making intramyocardial injection difficult. To resolve this contradiction, we developed molecular vehicles that combine a wrapped (rather than outer) polymer scaffold that is enveloped by the cell and provides excitability restoration (lost when cells were harvested) before engraftment. It also provides a coating with human fibronectin, which initiates the process of graft adhesion into the recipient tissue and can carry fluorescent markers for the external control of the non-invasive cell position. In this work, we used a type of scaffold that allowed us to use the advantages of a scaffold-free cell suspension for cell delivery. Fragmented nanofibers (0.85 µm ± 0.18 µm in diameter) with fluorescent labels were used, with solitary cells seeded on them. Cell implantation experiments were performed in vivo. The proposed molecular vehicles made it possible to establish rapid (30 min) electromechanical contact between excitable grafts and the recipient heart. Excitable grafts were visualized with optical mapping on a rat heart with Langendorff perfusion at a 0.72 ± 0.32 Hz heart rate. Thus, the pre-restored grafts' excitability (with the help of a wrapped polymer scaffold) allowed rapid electromechanical coupling with the recipient tissue. This information could provide a basis for the reduction of engraftment arrhythmias in the first days after cell therapy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Keloids are benign skin lesions that gradually invade the surrounding normal tissue, and no treatment has proven curative. In our previous clinical practice of autologous cultured fibroblast transplantation, we found that fibroblast injection might have some effect on treating keloids, and we attempted to treat keloids by using fibroblast transplantation after obtaining the patient’s approval. CASE REPORT: 1 patient was treated from March 2017 to June 2018. Autologous skin fibroblasts were separated from postauricular skin biopsy or resected keloid. They were cultured and expanded with exclusive methods. Cells (3×107/ml) within four or five passages were injected intradermally at the keloid at one-month intervals, 15 times in the patient. Shrink of the keloid on the patient was observed. The keloid became softer, flatter, and lighter in color after treatment. The elasticity of the keloid was also increased. The treatment effect was associated with the number of treatment sessions. CONCLUSIONS: This is the first report in which autologous fibroblast transplantation was used to treat keloids. Despite being only a single case experience, it suggests that keloid formation is a complex process in which still unknown factors may play a role. [ABSTRACT FROM AUTHOR]

Definition: Primary chondroprogenitors obtained from standardized cell sources (e.g., FE002 clinical grade cell sources) may be cultured in vitro and may be cytotherapeutically applied in allogeneic musculoskeletal regenerative medicine. Multicentric translational research on FE002 human primary chondroprogenitors under the Swiss progenitor cell transplantation program has notably validated their robustness and high versatility for therapeutic formulation in clinically compatible prototypes, as well as a good safety profile in diverse in vivo preclinical models. Therein, stringently controlled primary cell source establishment and extensive cell manufacturing optimization have technically confirmed the adequation of FE002 primary chondroprogenitors with standard industrial biotechnology workflows for consistent diploid cell biobanking under GMP. Laboratory characterization studies and extensive qualification work on FE002 progenitor cell sources have elucidated the key and critical attributes of the cellular materials of interest for potential and diversified human cytotherapeutic uses. Multiple formulation studies (i.e., hydrogel-based standardized transplants, polymeric-scaffold-based tissue engineering products) have shown the high versatility of FE002 primary chondroprogenitors, for the obtention of functional allogeneic cytotherapeutics. Multiple in vivo preclinical studies (e.g., rodent models, GLP goat model) have robustly documented the safety of FE002 primary chondroprogenitors following implantation. Clinically, FE002 primary chondroprogenitors may potentially be used in various forms for volumetric tissue replacement (e.g., treatment of large chondral/osteochondral defects of the knee) or for the local management of chondral affections and pathologies (i.e., injection use in mild to moderate osteoarthritis cases). Overall, standardized FE002 primary chondroprogenitors as investigated under the Swiss progenitor cell transplantation program were shown to constitute tangible contenders in novel human musculoskeletal regenerative medicine approaches, for versatile and safe allogeneic clinical cytotherapeutic management. [ABSTRACT FROM AUTHOR]

Cell transplants in therapeutic studies do not preserve their long-term function inside the donor body. In mesenchymal stem cell (MSC) transplants, transplanted cells disperse through the body and are prone to degradation by immune cells after the transplant process. Various strategies, such as usage of the immunosuppressive drugs to eliminate allograft rejection, are designed to increase the efficiency of cell therapy. Another strategy is the construction of biomimetic encapsulates using polymeric materials, which isolate stem cells and protect them from environmental effects. In this study, fibroblasts (L929) and MSCs were investigated for their improved viability and functionality once encapsulated inside the alginate microbeads under in vitro conditions for up to 12 days of incubation. Thus, uniform and injectable (<200 µm) cell-loaded microbeads were constructed by the electrostatically assisted spraying technique. Results showed that both L929 and MSCs cells continue their metabolic activity inside the microbeads during the incubation periods. Glucose consumption and lactic acid production levels of both cell lines were consistently observed. The released cell number on day 12 was found to be increased compared to day 0. Protein expression levels of both groups increased every day with the expected doubling rate. Hence, this strategy with a simple yet clever design to encapsulate either MSCs or L929 cells might outstand as a potential cell delivery platform for cell therapy-based tissue engineering. [ABSTRACT FROM AUTHOR]

Background: Despite the improvements in supportive care for allogeneic‐hematopoietic cell transplantation (allo‐HCT) recipients, infectious complications and infection‐related mortality (IRM) continue to be a major issue for transplantation centers. Methods: We herein report the infectious complications and IRM of 107 and 89 patients that underwent haploidentical (haplo‐HCT) or HLA‐identical HCT at a tertiary referral center during 2013‐2020. Patients in the haplo‐HCT group received post‐transplant cyclophosphamide (PT‐Cy), and all received reduced‐intensity conditioning regimens. Results: More haplo‐HCT recipients presented severe infections in the pre‐engraftment period (22.4% vs. 6.7%, p = 0.003). Viral (14.9% vs. 4.5%, p = 0.016) and fungal (12.1% vs. 1.1%, p = 0.003) etiologies were more common in this period in this group. The 100‐day and 2‐year cumulative incidence of IRM was 15% and 21% for the haplo‐HCT and 5.6% and 17% for the HLA‐identical group; no significant differences were observed between the groups. Fungal pathogens mainly contributed to IRM (33.3%). Infections were the most common cause of mortality (40/81, 49.4%). There were significant differences in donor/recipient CMV serostatus between transplant groups (0.002). Conclusions: No differences in IRM were observed based on allo‐HCT type, with more haplo‐HCT patients suffering from severe infections in the pre‐engraftment period. Studies to assess future prevention, diagnostic, and treatment strategies to reduce IRM are warranted. [ABSTRACT FROM AUTHOR]

Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies—such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells—that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies. [ABSTRACT FROM AUTHOR]