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Background Prior studies have demonstrated that relatively immature hematopoietic stem cells, including CD34 + CD38 - and CD34 +   HLA-DR - subsets, correlate with short-term hematopoietic reconstruction (SHR) after transplantation. The aim of this study was to investigate whether these immature CD34 + subsets also correlate with long-term hematopoietic reconstitution (LHR) in recipients of ABMT. Methods We examined stem cell grafts from 58 patients with B-cell lymphoma or CLL who underwent ABMT after myeloablative conditioning. We determined whether total mononuclear cell dose (MNC), colony-forming unit–granulocyte-monocyte (CFU-GM), CD34 + cell dose and CD34 + cell subsets (CD34 +   CD38 - and CD34 +   HLA-DR - ) were associated with SHR and/or LHR. Time to neutrophil engraftment (TNE) and time to platelet engraftment (TPE) were used to measure SHR, while platelet counts at day 100 and 1 year post-ABMT were used as indicators for LHR. Results and discussion CD34 + cell dose and CD34 + cell subsets were significantly associated with SHR. However, at day 100 and 1 year post-transplant only total CD34 + cell dose was associated with LHR. The association of total CD34 + cell dose with LHR persisted after adjusting for age, sex and disease. None of the CD34 + cell subsets analyzed showed evidence of significant association with LHR. [ABSTRACT FROM AUTHOR]

Background: Lumbar facet joint arthropathy (LFJA) is a major cause of low back pain (LBP), with current treatments offering limited long-term benefits. Bone marrow-derived mesenchymal stem cells (BM-MSCs) show promise due to their immunomodulatory and trophic effects, potentially addressing underlying degenerative processes in LFJA., Objectives: This initial report describes the outcomes of the first treated patient in an ongoing mutidisciplinary phase 1 clinical trial evaluating the safety and feasibility of intra-articular allogeneic BM-MSCs for painful LFJA., Methods: Following enrollment in our IRB-approved protocol, symptomatic LFJA was confirmed through double blocks on L4 and L5 medial branches. Two 1-mL syringes, each containing 10 million BM-MSCs, were prepared in the cGMP facility and administered bilaterally to the patient's L4-L5 lumbar facet joints. The patient underwent standardized follow-ups, including clinical examinations and functional and imaging assessments for 2 years, utilizing patient-reported outcomes measurement information system-computer adaptive tests (PROMIS CATs), visual analogue scale, Oswestry disability index, work functional status and opioid pain medication use, and MR imaging Fenton-Czervionke score., Results: The patient tolerated the procedure well, with no drug-related adverse events during the study period. Pain, spine function, and work functional status improved at multiple follow-ups. This patient also reported improvements in mental and social health, along with a notable improvement in the grade of facet synovitis observed at the one-year follow-up MRI evaluation., Conclusions: This case report suggests the safety and feasibility of administering intra-articular allogeneic BM-MSCs, offering therapeutic benefits for pain management and functional activities., Competing Interests: A.Q. is the founder of DOME Therapeutics. The other authors indicated no conflicts of interest.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Stem cell research performed in space has provided fundamental insights into stem cell properties and behavior in microgravity including cell proliferation, differentiation, and regeneration capabilities. However, there is broader scientific value to this research including potential translation of stem cell research in space to clinical applications. Here, we present important discoveries from different studies performed in space demonstrating the potential use of human stem cells as well as the limitations in cellular therapeutics. A full understanding of the effects of microgravity in space on potentially supporting the expansion and/or enhancement of stem cell function is required to translate the findings into clinics., (© 2024. The Author(s).)

Background: We conducted a preliminary phase I, dose-escalating, safety, and tolerability trial in the population of patients with acute intracerebral hemorrhage (ICH) by using human allogeneic bone marrow-derived mesenchymal stem/stromal cells., Methods: Eligibility criteria included nontraumatic supratentorial hematoma less than 60 mL and Glasgow Coma Scale score greater than 5. All patients were monitored in the neurosciences intensive care unit for safety and tolerability of mesenchymal stem/stromal cell infusion and adverse events. We also explored the use of cytokines as biomarkers to assess responsiveness to the cell therapy. We screened 140 patients, enrolling 9 who met eligibility criteria into three dose groups: 0.5 million cells/kg, 1 million cells/kg, and 2 million cells/kg., Results: Intravenous administration of allogeneic bone marrow-derived mesenchymal stem/stromal cells to treat patients with acute ICH is feasible and safe., Conclusions: Future larger randomized, placebo-controlled ICH studies are necessary to validate this study and establish the effectiveness of this therapeutic approach in the treatment of patients with ICH., (© 2023. The Author(s).)

Background: Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, and premature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC (iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines., Methods: We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit., Results: Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment., Conclusions: The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation., (© 2024. The Author(s).)

Study Design: Human bone marrow stem cells (hBMSCs) and human adipose-derived stem cells (hADSCs) have demonstrated the capability to regenerate bone once they have differentiated into osteoblasts., Objective: This systematic review aimed to evaluate the in vitro osteogenic differentiation potential of these cells when seeded in a poly (lactic- co -glycolic) acid (PLGA) scaffold., Methods: A literature search of 4 databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted in January 2021 for studies evaluating the osteogenic differentiation potential of hBMSCs and hADSCs seeded in a PLGA scaffold. Only in vitro models were included. Studies in languages other than English were excluded., Results: A total of 257 studies were identified after the removal of duplicates. Seven articles fulfilled our inclusion and exclusion criteria. Four of these reviews used hADSCs and three used hBMSCs in the scaffold. Upregulation in osteogenic gene expression was seen in all the cells seeded in a 3-dimensional scaffold compared with 2-dimensional films. High angiogenic gene expression was found in hADSCs. Addition of inorganic material to the scaffold material affected cell performance., Conclusions: Viability, proliferation, and differentiation of cells strongly depend on the environment where they grow. There are several factors that can enhance the differentiation capacity of stem cells. A PLGA scaffold proved to be a biocompatible material capable of boosting the osteogenic differentiation potential and mineralization capacity in hBMSCs and hADSCs., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: Despite numerous measures used to prevent pressure ulcers, their growing prevalence in recent years is expected to continue as the population ages. This review aims to report the outcomes of the regenerative potential of MSCs in treating pressure ulcers, assessing the effectiveness of MSCs in treating pressure ulcers., Methods: A computerized search for articles on animal models that use MSCs as primary therapy to treat pressure ulcers, published from conception to present, was conducted using PubMed, MEDLINE, Embase, and CINAHL. Our search yielded 52 articles, narrowed to 44 after excluding duplicates., Results: Out of 52 articles collected from four databases, 11 met the inclusion criteria. A total of 11 articles published between 2008 and 2020 met the inclusion criteria. Eight studies were observational descriptive papers in animal models, and three were prospective. Six studies used autologous MSCs, while five used allogenic MSCs. Three studies were conducted in humans, and the remaining eight were conducted in animals. The most common method of cell delivery was an intradermal injection in the margins of the ulcer. All studies reported positive results, including improved wound healing, reduced inflammation, and improved tissue regeneration., Conclusions: MSCs have shown promising results in treating pressure ulcers in animal and clinical trials. The combination of MSCs and scaffold materials has also been studied and found to be effective in wound healing. A standardized human wound model has been proposed further to investigate the efficacy of cell-based therapies for chronic wounds. However, more research is needed to determine the best quantity of cells to apply for pressure ulcers and to ensure the safety and efficacy of these treatments in clinical settings.

Background and Objectives: Despite standard of care with maximal safe resection and chemoradiation, glioblastoma is the most common and aggressive type of primary brain cancer. Surgical resection provides a window of opportunity to locally treat gliomas while the patient is recovering, and before initiating concomitant chemoradiation. To assess the safety and establish the maximum tolerated dose of adipose-derived mesenchymal stem cells (AMSCs) for the treatment of recurrent glioblastoma (GBM). Secondary objectives are to assess the toxicity profile and long-term survival outcomes of patients enrolled in the trial. Additionally, biospecimens will be collected to explore the local and systemic responses to this therapy., Methods: We will conduct a phase 1, dose escalated, non-randomized, open label, clinical trial of GBM patients who are undergoing surgical resection for recurrence. Up to 18 patients will receive intra-cavitary application of AMSCs encapsulated in fibrin glue during surgical resection. All patients will be followed for up to 5 years for safety and survival data. Adverse events will be recorded using the CTCAE V5.0., Expected Outcomes: This study will explore the maximum tolerated dose (MTD) of AMSCs along with the toxicity profile of this therapy in patients with recurrent GBM. Additionally, preliminary long-term survival and progression-free survival outcome analysis will be used to power further randomized studies. Lastly, CSF and blood will be obtained throughout the treatment period to investigate circulating molecular and inflammatory tumoral/stem cell markers and explore the mechanism of action of the therapeutic intervention., Discussion: This prospective translational study will determine the initial safety and toxicity profile of local delivery of AMSCs for recurrent GBM. It will also provide additional survival metrics for future randomized trials., Competing Interests: Disclosures: The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. Alfredo Quiñones-Hinojosa and Jordan J. Green are co-founders with equity and Managers of the startup company Dome Therapeutics.

Due to the advent of effective novel therapies for multiple myeloma (MM), the use of cryopreserved autologous peripheral blood hematopoietic cells (APBHC) for a salvage autologous transplant (auto-HCT) is in decline. We evaluated utilization trends and costs associated with cryopreserved APBHC in patients with MM. We retrospectively evaluated the clinicopathologic data from 440 patients with MM who underwent APBHC mobilization and collection at Mayo Clinic Florida between 2010 and 2019. Based on institution-specific charges as of May 2021, the cost of 1 session of APBHC collection/apheresis was $4,680 and the cost of 1 year of APBHC cryopreservation was $4,790 per patient. Out of 347 patients who had APBHC in cryopreservation, 5 (1.4%) underwent a salvage auto-HCT and 61% of patients had ≥1 excess collection sessions for APBHC that ultimately went unused. The median cost of excess collection sessions was $4,680 per patient (range, $4,680-$32,760) and the median total cost for excess collection sessions plus costs for storage was $23,840 per patient (range, $4,680-$85,450). The sum of costs of excess collection sessions was $2,077,920 and the sum of costs of cryopreservation was $5,812,665. Institutional policies regarding universal APBHC collection and long-term storage should be reevaluated in the era of novel therapeutics., (© 2023. The Author(s).)

Background: The use of bone morphogenic protein and mesenchymal stem cells has shown promise in promoting bone regeneration in calvarial defects. However, a systematic review of the available literature is needed to evaluate the efficacy of this approach., Methods: We comprehensively searched electronic databases using MeSH terms related to skull defects, bone marrow mesenchymal stem cells, and bone morphogenic proteins. Eligible studies included animal studies that used BMP therapy and mesenchymal stem cells to promote bone regeneration in calvarial defects. Reviews, conference articles, book chapters, and non-English language studies were excluded. Two independent investigators conducted the search and data extraction., Results: Twenty-three studies published between 2010 and 2022 met our inclusion criteria after a full-text review of the forty-five records found in the search. Eight of the 23 studies used mice as models, while 15 used rats. The most common mesenchymal stem cell was bone marrow-derived, followed by adipose-derived. BMP-2 was the most popular. Stem cells were embedded in Scaffold (13), Transduction (7), and Transfection (3), and they were delivered BMP to cells. Each treatment used 2 × 10 4 -1 × 10 7 mesenchymal stem cells, averaging 2.26 × 10 6 . Most BMP-transduced MSC studies used lentivirus., Conclusions: This systematic review examined BMP and MSC synergy in biomaterial scaffolds or alone. BMP therapy and mesenchymal stem cells in calvarial defects, alone, or with a scaffold regenerated bone. This method treats skull defects in clinical trials. The best scaffold material, therapeutic dosage, administration method, and long-term side effects need further study.

Background: Therapeutic interventions that optimize angiogenic activities may reduce rates of end-stage kidney disease, critical limb ischemia, and lower extremity amputations in individuals with diabetic kidney disease (DKD). Infusion of autologous mesenchymal stromal cells (MSC) is a promising novel therapy to rejuvenate vascular integrity. However, DKD-related factors, including hyperglycemia and uremia, might alter MSC angiogenic repair capacity in an autologous treatment approach., Methods: To explore the angiogenic activity of MSC in DKD, the transcriptome of adipose tissue-derived MSC obtained from DKD subjects was compared to age-matched controls without diabetes or kidney impairment. Next-generation RNA sequencing (RNA-seq) was performed on MSC (DKD n = 29; Controls n = 9) to identify differentially expressed (DE; adjusted p < 0.05, |log 2 fold change|> 1) messenger RNA (mRNA) and microRNA (miRNA) involved in angiogenesis (GeneCards). Paracrine-mediated angiogenic repair capacity of MSC conditioned medium (MSCcm) was assessed in vitro using human umbilical vein endothelial cells incubated in high glucose and indoxyl sulfate for a hyperglycemic, uremic state., Results: RNA-seq analyses revealed 133 DE mRNAs (77 upregulated and 56 down-regulated) and 208 DE miRNAs (119 up- and 89 down-regulated) in DKD-MSC versus Control-MSC. Interestingly, miRNA let-7a-5p, which regulates angiogenesis and participates in DKD pathogenesis, interacted with 5 angiogenesis-associated mRNAs (transgelin/TAGLN, thrombospondin 1/THBS1, lysyl oxidase-like 4/LOXL4, collagen 4A1/COL4A1 and collagen 8A1/COL8A1). DKD-MSCcm incubation with injured endothelial cells improved tube formation capacity, enhanced migration, reduced adhesion molecules E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 mRNA expression in endothelial cells. Moreover, angiogenic repair effects did not differ between treatment groups (DKD-MSCcm vs. Control-MSCcm)., Conclusions: MSC from individuals with DKD show angiogenic transcriptome alterations compared to age-matched controls. However, angiogenic repair potential may be preserved, supporting autologous MSC interventions to treat conditions requiring enhanced angiogenic activities such as DKD, diabetic foot ulcers, and critical limb ischemia., (© 2023. The Author(s).)

Background: We have previously shown bone marrow-derived mesenchymal stem cells (MSCs) may shift immune responses toward anti-inflammatory pathways and stabilize the course of obstructive chronic lung allograft syndrome (o-CLAD) after lung transplantation. In this study, we measured the response of lower dose infusions., Methods: We infused low-dose MSCs intravenously in 13 patients who had developed moderate-to-severe o-CLAD. Three had previously received an infusion of MSCs from a different donor and were re-dosed at 1 × 106 MSC/kg, while 5 received a first dose at 1 × 106 MSC/kg and five received an even lower dose at 0.5 × 106 MSC/kg. We recorded pulmonary function tests before and after infusion, and patients were followed clinically for 12 months., Results: Infusions were well tolerated, and no significant adverse events were recorded in the first 30 days. There was significant decline (mean ± SD) in forced vital capacity (FVC) (3.49 ± 1.03 vs 3.18 ± 0.94 L, P = .03) and forced expiratory volume in 1 second (FEV1) (2.28 ± 0.86 vs 1.77 ± 0.49 L, P = .04) over the year preceding infusion. FVC (3.18 ± 0.94 vs 3.46 ± 0.99 L, P = .53) and FEV1 was not significantly changed (1.77 ± 0.49 vs 1.88 ± 0.75, P = .72) when comparing values immediately prior to infusion to those obtained 1 year after infusion, indicating a possible stabilizing effect on lung function decline due to o-CLAD., Conclusion: Intravenous infusions of bone marrow-derived MSCs are well tolerated in lung transplant recipients with moderate-to-severe CLAD. Low-dose MSCs appear to slow progression of CLAD in some patients., (© The Author(s) 2022. Published by Oxford University Press.)

Background Aims: This white paper was developed to provide leukapheresis guidance for the collection of mononuclear cells from adult and pediatric patients who are destined for immune effector cell (IEC) therapies for commercial and research applications. Currently, there is considerable variability in leukapheresis processes and limited published information regarding best practices relevant to new cellular therapies, especially IECs. Herein the authors address critical leukapheresis questions in five domains to help guide consistent collection processes and ensure high-quality products. The first four domains are onboarding, pre-collection, collection and post-collection, with protocol feasibility, preparation, care and follow-up of the patient/donor at each step, respectively, and technical considerations during collection. The fifth domain of quality assurance focuses on ensuring product potency, purity, safety and auditing., Methods: The American Society for Apheresis (ASFA) Clinical Applications Committee (IEC Therapy Subcommittee) was charged by the society's board of directors with working collaboratively with other ASFA committees and organizations, including the Foundation for the Accreditation of Cellular Therapy, Association for the Advancement of Blood and Biotherapies, American Society for Transplantation and Cellular Therapy, National Marrow Donor Program and International Society for Cell & Gene Therapy, to develop guidelines regarding leukapheresis collection of cells destined for the manufacture of IEC therapies. After a review of the literature and discussion with members of the involved committees and various institutions, a draft guidance was created and circulated for comment and revision., Results: Critical aspects of apheresis that could affect the quality and quantity of the leukapheresis product were identified. These areas were then discussed and reviewed. After consensus, the best practice guidelines were proposed and accepted., Conclusions: In the current era of rapid growth of IEC therapies, it is important to address critical leukapheresis steps to provide high-quality products and more consistent practices and to eliminate redundant efforts., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2022 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Drug-resistant epilepsy (DRE) is characterized by recurrent seizures despite appropriate treatment with antiseizure medication (ASM). Due to their regenerative and immunomodulatory potential, therapies with biologics such as mesenchymal stem cells (MSCs) offer a potential therapeutic benefit for structural causes of epilepsy, such as hippocampal sclerosis. In this article, we report a systematic review of the literature evaluating the preclinical and clinical studies of MSCs for DRE. Medline, Ovid EMBASE, Scopus, and the Cochrane Databases were searched electronically from their dates of inception to November 2021 using the following keywords: (("mesenchymal") AND ("stem cell")) AND (("epilepsy") OR ("convulsion") OR ("seizures")). This review followed Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines. The initial query identified 488 studies representing 323 unique manuscripts. After application of selection criteria, 15 studies were included in this systematic review; 11 were preclinical studies and 4 were clinical studies. All preclinical studies were performed in rodents and all clinical studies were phase 1 trials. Thus far, therapy with MSCs appears to be safe for use in humans, as no severe adverse events related directly to the therapy were reported. Furthermore, MSC therapy appears to provide a statistically significant clinical benefit by reducing the seizure burden of patients, reducing the electrophysiological biomarkers of epilepsy, and improving their comorbidities, such as depression and anxiety. In addition, animal studies reveal that the therapy exerts its effect by reducing aberrant mossy fiber sprouting (reduce excitatory pathways) and increasing γ-aminobutyric acid (GABA)ergic interneurons (increase inhibitory pathways). Both preclinical and clinical studies have shown MSC therapy to be safe and preliminary effective, thus warranting further studies to investigate its therapeutic potential., (© 2022 International League Against Epilepsy.)

Background: Chimeric antigen receptor T (CAR-T) cell successes have encouraged continued clinical study. Apheresis collection of starting material for CAR-T cell therapy product manufacturing is critical but described approaches suggest variability and clinical guidelines are currently lacking. The goal of this study was to gather and assess variability in apheresis collection descriptions in publicly available CAR T-cell therapy clinical trials., Study Design: We searched clinicaltrials.gov (a publicly available clinical trial database) for "chimeric antigen receptor T cells" on July 01, 2020 and studies accessed July 30, 2020-August 15, 2020. Data collected included date posted, study characteristics, apheresis mentions (number, location, and context), laboratory parameters and transfusion allowances. Apheresis context was analyzed using a qualitative inductive approach of grounded theory method with open coding. Text was classified into 37 context codes, grouped into 12 categories, and then consolidated into patient, procedure, product, and miscellaneous themes., Results: Apheresis was mentioned 1044 times in 322 (51.9%) of 621 total studies. Laboratory parameters mentioned included white blood cells (100 studies), absolute neutrophil count (220 studies), absolute lymphocyte count (102 studies), CD3 + cell (38 studies), hemoglobin (233 studies, 54 studies specified transfusion allowance), and platelet (269 studies, 48 studies specified transfusion allowance)., Conclusions: Apheresis collection of CAR-T cell products is not well-defined in clinical study descriptions and the context is inconsistent. Laboratory parameters useful for apheresis collection are variably present and do not consistently align with current practices. Further exploration, and clinical guideline development will encourage alignment of apheresis collections for CAR-T cell products., (© 2022 Wiley Periodicals LLC.)

Background Aims: Mesenchymal stromal cells (MSCs) remain an area of interest in the field of regenerative medicine. Although there is clear evidence of safety, a lack of substantial efficacy has led to many MSC-based clinical trials to stall in phase 1. Therefore, potentiating MSCs with biologically relevant messenger RNA (mRNA) transcripts presents a relatively safe and efficient way to increase functionality., Methods: In this study, human bone marrow-derived MSCs were transfected with endothelial nitric oxide synthase (eNOS) mRNA and evaluated for transfection efficiency and immunosuppressive ability. To assess MSC-eNOS functionality, T-cell proliferation assays and mouse models of experimental autoimmune encephalomyelitis and graft-versus-host disease were used., Results: The authors found that MSC-eNOS retained MSC characteristics and exhibited significantly enhanced immunosuppressive effects compared with naive MSCs in both in vitro and in vivo models., Conclusions: It is feasible to pursue eNOS mRNA transfection to potentiate the immunomodulatory capacity of MSCs for clinical applications in the future., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2021 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Adipose-derived mesenchymal stem cells (ADSCs) have been proven effective to prevent distal skin flap necrosis in preclinical models. However, to appropriately translate these findings to clinical trials, the effect of ADSC of human origin (hADSC) needs to be evaluated. We hypothesize that hADSC treatment is as effective as animal ADSC treatment at preventing distal skin flap necrosis in animal flap models., Methods: Three databases were inquired on August 17, 2020, to evaluate the necrotic flap area after using hADSCs in animal models of ischemic flaps. No publication status or dates were considered. Studies were included if they used hADSCs, measured the surviving or necrotic skin area of flaps, used animal models, and were in English. Studies were excluded if they did not use cells of human origin. The flap survival or necrotic area, perfusion, capillary density, vascular endothelial growth factor secretion and HIF-1α expression were extracted., Results: Ten studies met inclusion criteria. The mean absolute risk reduction (ARR) in necrotic skin area was 22.37% (95% confidence interval [CI] 16.98-27.76%, P <0.05) for flaps treated with animal ADSCs and 18.04% (95% CI 2.74-33.33%, P<0.05) for flaps treated with hADSCs. The difference between mean ARRs was not statistically significant (4.33%, 95% CI - 34.47-43.13%, P >0.05)., Conclusion: Human ADSCs prevent skin flap necrosis to the same degree as animal ADSCs in rodent and rabbit flap models., Relevance for Patients: This review found that adipose-derived stem cells of human origin are equally effective at reducing the risk of surgical flap necrosis in preclinical models of small animals as autologous animal cells. The findings in this review should encourage researchers to use human adipose-derived stem cells in animal models of ischemic flaps to accelerate their translation into clinical trials and, eventually, surgical practice. The low immunogenicity of these cells should be leveraged to gain insight into the effects of the products that will be ultimately administered to patients. Furthermore, human adipose-derived stem cells' pro-angiogenic mechanism of action sets this therapy as a promising preventive measure for flap necrosis., Competing Interests: The authors report no conflicts of interest., (Copyright: © 2022 Whioce Publishing Pte. Ltd.)

Mesenchymal stem/stromal cell (MSC) therapy has been investigated in multiple diseases and conditions. Although the mechanisms of MSC-based therapies are not fully understood, we and others have shown interleukin 6 (IL-6) to be an important factor in MSC function. IL-6 contributes to many biological events, such as immune response, neurogenesis, and bone remodeling. In our study, we tested the feasibility of engineering MSCs by IL-6 mRNA transfection (eMSCs-IL6) and evaluated the optimal time to harvest them after transfection. We then assessed the functional characteristics of eMSCs-IL6. Quantitative real-time PCR and ELISA results have shown that mature IL-6 mRNA was efficiently transfected into MSCs using a lipofectamine based method. The IL-6 mRNA and protein overexpression peaked after 1 day of transfection and the secreted IL-6 protein was sustained for at least 6 days. A short time course experiment demonstrated that 4 h after transfection was the best time point to harvest and freeze eMSCs-IL6 for future studies. In addition, eMSCs-IL6 maintained their characteristics as defined by International Society for Cell & Gene Therapy. The immunosuppressive capacity of conditioned culture medium (CCM) from eMSCs-IL6 (CCM-IL6) was significantly enhanced compared to naïve MSCs conditioned culture medium (CCM-control). Our studies established for the first time the feasibility of efficiently generating IL-6 overexpressing MSCs which have enhanced immunosuppressive capacity. This is providing a novel approach to improve the efficacy of MSCs for potential application in regenerative medicine., (© 2021 John Wiley & Sons Ltd.)

Background: Human adipose-derived stem cells (hADSCs) have gained attention lately because of their ease of harvesting and ability to be substantially multiplied in laboratory cultures. Stem cells are usually cultured under atmospheric conditions; however, preconditioning stem cells under hypoxic conditions seems beneficial., Aim: This systematic review aims to investigate the effect of hypoxia preconditioning and its impact on the proliferation and angiogenic capacity of the hADSCs., Methods: We performed a systematic review by searching PubMed, Scopus, Embase, and Google Scholar databases from all years through March 22, 2021, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Medical Subject Headings terms "adipose-derived stem cell," "Hypoxia," "cell proliferation," and "angiogenesis" guided our search. Only articles written in English using experimental models comparing a preconditioned group against a control group of hADSCs with data on proliferation and angiogenic capacity were included., Results: Our search yielded a total of 321 articles. 11 articles met our inclusion criteria and were ultimately included in this review. Two studies induced hypoxia using hypoxia-inducible factor-1 alpha stabilizing agents, while nine reached hypoxia by changing oxygen tension conditions around the cells. Four articles conducted in-vivo studies to correlate their in-vitro findings, which proved to be consistent. Although 1 article indicated cell proliferation inhibition with hypoxia preconditioning, the remaining 10 found enhanced proliferation in preconditioned groups compared to controls. All articles showed an enhanced angiogenic capacity of hADSCs after hypoxia preconditioning., Conclusion: In this review, we found evidence to support hypoxia preconditioning of hADSCs before implantation. Benefits include enhanced cell proliferation with a faster population doubling rate and increased secretion of multiple angiogenic growth factors, enhancing angiogenesis capacity., Relevance for Patients: Although regenerative therapy is a promising field of study and treatment in medicine, much is still unknown. The potential for angiogenic therapeutics with stem cells is high, but more so, if we discover ways to enhance their natural angiogenic properties. Procedures and pathologies alike require the assistance of angiogenic treatments to improve outcome, such is the case with skin grafts, muscle flaps, skin flaps, or myocardial infarction to mention a few. Enhanced angiogenic properties of stem cells may pave the way for better outcomes and results for patients., Competing Interests: The authors declare no conflict of interest, (Copyright: © Whioce Publishing Pte. Ltd.)

Background: Archeological archives report cranioplasty as 1 of the oldest surgical procedures; however, it was not until the last century that true advances have been made. Alternative approaches are necessary to achieve optimal closure of the defect with fewer adverse effects. We aim to evaluate the use of human adipose-derived stem cells (hADSCs) alone or seeded in scaffolds as the main treatment for cranial bone defects and to assess human patient outcomes., Methods: A systematic review was performed by querying PubMed, Ovid MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature databases with the MeSH terms: "adipose-derived stem cells," "cranial bone defect," "stromal vascular factor," "fat grafting," as well as synonyms in combinations determined by our search strategy. We included human models that used hADSCs as primary therapy. We excluded studies in languages other than English., Results: One hundred ninety-four studies were identified after removal of duplicates. Four articles that used hADSCs as the main therapy to treat calvarial defects in humans were included. One article applied the cell therapy alone, and 3 used β-tricalcium phosphate granules as a scaffold to seed the hADSCs., Conclusions: Bone regeneration was reached in a short and intermediate period using autologous hADSCs in humans with no major adverse effects in all 4 articles included. A long-term follow-up study (6 years) exhibited late infections and reabsorption of the β-tricalcium phosphate scaffold seeded with hADSCs., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by Mutaz B. Habal, MD.)

Mesenchymal stem cells (MSCs) are used in various studies to induce immunomodulatory effects in clinical conditions associated with immune dysregulation such as graft versus host disease (GvHD). However, most of these clinical trials failed to go beyond early phase 2 studies because of limited efficacy. Various methods have been assessed to increase the potency of MSCs. IL-10 is an anti-inflammatory cytokine that is known to modulate immune responses in GvHD. In this study, we evaluated the feasibility of transfecting IL-10 mRNA to enhance MSC therapeutic potential. IL-10 mRNA engineered MSCs (eMSCs-IL10) maintained high levels of IL-10 expression even after freezing and thawing. IL-10 mRNA transfection did not appear to alter MSC intrinsic characteristics. eMSCs-IL10 significantly suppressed T cell proliferation relative to naïve MSCs in vitro. In a mouse model for GvHD, eMSCs-IL10 induced a decrease in plasma level of potent pro-inflammatory cytokines and inhibited CD4+ and CD8+ T cell proliferation in the spleen. In summary, our studies demonstrate the feasibility of potentiating MSCs to enhance their immunomodulatory effects by IL-10 mRNA transfection. The use of non-viral transfection may generate a safe and potent MSC product for treatment of clinical conditions associated with immune dysregulation such as GvHD.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the presence of Lewy bodies, which gives rise to motor and non-motor symptoms. Unfortunately, current therapeutic strategies for PD merely treat the symptoms of the disease, only temporarily improve the patients' quality of life, and are not sufficient for completely alleviating the symptoms. Therefore, cell-based therapies have emerged as a novel promising therapeutic approach in PD treatment. Mesenchymal stem/stromal cells (MSCs) have arisen as a leading contender for cell sources due to their regenerative and immunomodulatory capabilities, limited ethical concerns, and low risk of tumor formation. Although several studies have shown that MSCs have the potential to mitigate the neurodegenerative pathology of PD, variabilities in preclinical and clinical trials have resulted in inconsistent therapeutic outcomes. In this review, we strive to highlight the sources of variability in studies using MSCs in PD therapy, including MSC sources, the use of autologous or allogenic MSCs, dose, delivery methods, patient factors, and measures of clinical outcome. Available evidence indicates that while the use of MSCs in PD has largely been promising, conditions need to be standardized so that studies can be effectively compared with one another and experimental designs can be improved upon, such that this body of science can continue to move forward.

The field of regenerative medicine has expanded greatly in the past decade, with more than 1000 current clinical trials involving mesenchymal stromal cell (MSC) treatment. Multiple recent publications have demonstrated that the beneficial effects from MSCs are not simply due to engraftment into the target organ as classically thought but rather are largely attributable to the release of paracrine factors including cytokines, growth factors and extracellular vesicles (EVs). These EVs contain miRNAs, free fatty acids and proteins that promote regeneration, proliferation and cell function and improve inflammation. Although EVs have shown promising results in animal studies, there are many obstacles to the manufacturing of EVs for clinical applications. This review discusses challenges associated with the manufacturing of clinical-grade EVs in regard to identity, purity, reproducibility, sterility, storage, potency and safety. We discuss currently employed methods and approaches for developing clinical Good Manufacturing Practices (GMP)-grade EVs and the limitations for each. We further discuss the best approaches to overcome the current hurdles in developing clinical GMP-grade EVs., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The emergence of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) at the end of 2019 in Hubei province China, is now the cause of a global pandemic present in over 150 countries. COVID-19 is a respiratory illness with most subjects presenting with fever, cough and shortness of breath. In a subset of patients, COVID-19 progresses to hypoxic respiratory failure and acute respiratory distress syndrome (ARDS), both of which are mediated by widespread inflammation and a dysregulated immune response. Mesenchymal stem cells (MSCs), multipotent stromal cells that mediate immunomodulation and regeneration, could be of potential benefit to a subset of COVID-19 subjects with acute respiratory failure. In this review, we discuss key features of the current COVID-19 outbreak, and the rationale for MSC-based therapy in this setting, as well as the limitations associated with this therapeutic approach.

Severe cases of COVID-19 infection, often leading to death, have been associated with variants of acute respiratory distress syndrome (ARDS). Cell therapy with mesenchymal stromal cells (MSCs) is a potential treatment for COVID-19 ARDS based on preclinical and clinical studies supporting the concept that MSCs modulate the inflammatory and remodeling processes and restore alveolo-capillary barriers. The authors performed a systematic literature review and random-effects meta-analysis to determine the potential value of MSC therapy for treating COVID-19-infected patients with ARDS. Publications in all languages from 1990 to March 31, 2020 were reviewed, yielding 2691 studies, of which nine were included. MSCs were intravenously or intratracheally administered in 117 participants, who were followed for 14 days to 5 years. All MSCs were allogeneic from bone marrow, umbilical cord, menstrual blood, adipose tissue, or unreported sources. Combined mortality showed a favorable trend but did not reach statistical significance. No related serious adverse events were reported and mild adverse events resolved spontaneously. A trend was found of improved radiographic findings, pulmonary function (lung compliance, tidal volumes, PaO 2 /FiO 2 ratio, alveolo-capillary injury), and inflammatory biomarker levels. No comparisons were made between MSCs of different sources., (© 2020 The Authors. STEM CELLS TRANSLATIONAL MEDICINE published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Blood plasma is a readily accessible source of extracellular vesicles (EVs), i.e., cell-secreted nanosized carriers that contain various biomolecules, including glycans. Previous studies have demonstrated that glycans play a major role in physiological and pathological processes, and certain plasma glycans have been associated with disease conditions. However, glycome studies have been limited by a lack of analytical techniques with the throughput capacity necessary to study hundreds of clinical samples. This study is the first to characterize the EV plasma glycome based on all major glycan classes. The results based on glycan node analysis revealed, as expected, that plasma-derived EVs have distinct glycan features from donor-matched whole plasma. Specifically, glycan nodes corresponding to those observed in chondroitin sulfate, dermatan sulfate, type I keratan sulfate, and type II keratan sulfate were enriched on EVs. The identification of specific differences in glycan features in plasma vs. plasma-derived EVs is relevant for understanding the physiological role of EVs and as a reference for future diagnostic studies. Additionally, the results indicate that EV glycan nodes do not substantially differ among a small set of healthy donors. These results lay the framework for the further evaluation of all EV glycan classes as diagnostic markers, therapeutic targets, and biologically active components in health and disease.

Growing stem cells on Earth is very challenging and limited to a few population doublings. The standard two-dimensional (2D) culture environment is an unnatural condition for cell growth. Therefore, culturing stem cells aboard the International Space Station (ISS) under a microgravity environment may provide a more natural three-dimensional environment for stem cell expansion and organ development. In this study, human-derived mesenchymal stem cells (MSCs) grown in space were evaluated to determine their potential use for future clinical applications on Earth and during long-term spaceflight. MSCs were flown in Plate Habitats for transportation to the ISS. The MSCs were imaged every 24-48 h and harvested at 7 and 14 days. Conditioned media samples were frozen at -80 °C and cells were either cryopreserved in 5% dimethyl sulfoxide, RNAprotect, or paraformaldehyde. After return to Earth, MSCs were characterized to establish their identity and cell cycle status. In addition, cell proliferation, differentiation, cytokines, and growth factors' secretion were assessed. To evaluate the risk of malignant transformation, the space-grown MSCs were subjected to chromosomal, DNA damage, and tumorigenicity assays. We found that microgravity had significant impact on the MSC capacity to secrete cytokines and growth factors. They appeared to be more potent in terms of immunosuppressive capacity compared to their identical ground control. Chromosomal, DNA damage, and tumorigenicity assays showed no evidence of malignant transformation. Therefore, it is feasible and potentially safe to grow MSCs aboard the ISS for potential future clinical applications., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

Background Recent studies of patients with intracerebral hemorrhage suggest an association between peripheral blood neutrophil-lymphocyte ratio and neurologic deterioration. We aimed to study the prognostic utility of neutrophil-lymphocyte ratio in predicting inpatient mortality in aneurysmal subarachnoid hemorrhage. Methods We conducted a retrospective electronic medical record review of the clinical, laboratory, and radiographic data of patients with aneurysmal subarachnoid hemorrhage 18 years of age or older presenting to the neuroscience intensive care unit from January 1, 2011, to December 31, 2017. Patients with aneurysmal subarachnoid hemorrhage were divided into 2 groups (group 1, alive at discharge; group 2, deceased prior to discharge), and neutrophil-lymphocyte ratio laboratory mean values were recorded for each patient. Our primary outcome measure was inpatient mortality, and our secondary measure was incidence of pneumonia with hospitalization. Results We identified 403 patients with aneurysmal subarachnoid hemorrhage for the study. After exclusion criteria, 44 eligible patients were divided into the 2 groups (group 1, n = 32; group 2, n = 12). Mean neutrophil-lymphocyte ratio for group 1 was 11.53, and for group 2, 17.85 (P < .01). The mean neutrophil-lymphocyte ratio of those who developed pneumonia compared to those who did not was 15.28 versus 12.81, respectively (P = .39). A Kaplan-Meier plot demonstrated increased mortality among patients with a neutrophil-lymphocyte ratio equal to or greater than 12.5 compared to those with a neutrophil-lymphocyte ratio less than 12.5. Conclusions These preliminary data demonstrate that a neutrophil-lymphocyte ratio equal to or greater than 12.5 at admission predict higher inpatient mortality in patients with aneurysmal subarachnoid hemorrhage., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background Aims: Baseline platelet count has been shown to be a sensitive predictor of autologous peripheral blood progenitor cell collection yield in patients with multiple myeloma mobilized with granulocyte colony-stimulating factor (G-CSF). Patients who mobilize poorly with G-CSF are often treated with plerixafor to enhance mobilization. There are no surrogate markers available to predict response to plerixafor., Methods: We retrospectively analyzed data from 73 patients with multiple myeloma who did not have adequate mobilization with G-CSF alone and were treated with plerixafor as a rescue agent., Results: We found that baseline platelet count directly correlated with peripheral blood CD34 + (PB-CD34 + ) count after plerixafor treatment (r = 0.36, P < 0.0001) and the number of PB-CD34 + cells collected on the first day of apheresis and inversely correlated with the number of apheresis sessions needed to collect the target number of PB-CD34 + cells (P = 0.0015). Baseline platelet count of 153 000/µL or less was associated with 90% specificity of predicting poor response to plerixafor with a sensitivity of 33%., Conclusions: Baseline platelet count is a good predictor of mobilization response to plerixafor in patients with multiple myeloma., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article. Mayo Clinic does not endorse specific products or services included in this article., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: Bone marrow aspiration and concentration (BMAC) is becoming a more common regenerative therapy for musculoskeletal pathology. In our current pilot study, we studied patients with mild-to-moderate bilateral knee osteoarthritis, compared pain at 12-month follow-up between BMAC-injected and saline-injected knees, and examined cartilage appearance measured by magnetic resonance imaging (MRI) T2 quantitative mapping., Design: Twenty-five patients with mild-to-moderate bilateral osteoarthritic knee pain were randomized to receive BMAC into one knee and saline placebo into the other. Bone marrow was aspirated from the iliac crests, concentrated in an automated centrifuge, combined with platelet-poor plasma for knee injection, and compared with saline injection into the contralateral knee. Primary outcome measures were T2 MRI cartilage mapping at 6-month and Visual Analog Scale and Osteoarthritis Research Society International Intermittent and Constant Osteoarthritis Pain scores and radiographs at 12-month follow-up., Results: Constant, intermittent, and overall knee pain remained significantly decreased from baseline at 12-month follow-up (all P ⩽ 0.01), with no apparent difference between BMAC- and saline-treated knees (all P ⩾ 0.54). A similar significant increase from baseline to 12-month follow-up regarding quality of life was observed for both BMAC- and saline-treated knees (all P ⩽ 0.04). T2 quantitative MRI mapping showed no significant changes as a result of treatment., Conclusions: BMAC is safe to perform and relieves pain from knee arthritis but showed no superiority to saline injection at 12-month follow-up. MRI cartilage sequences failed to show regenerative benefit with single BMAC injection. The mechanisms of action that led to pain relief remain unclear and warrant further studies.

Cellular and cell-derived components of adipose-derived tissue for the purposes of dermatologic and aesthetic rejuvenation applications have become increasingly studied and integrated into clinical practice. These components include micro-fragmented fat (nanofat), the stromal vascular fraction (SVF), adipose-derived mesenchymal stem cells (ASC), and extracellular vesicles (EVs), which have all shown capability to repair, regenerate, and rejuvenate surrounding tissue. Various aesthetic applications including hair growth, scar reduction, skin ischemia-reperfusion recovery, and facial rejuvenation are reviewed. In particular, results from preclinical and clinical studies are discussed, with a focus on clarification of nomenclature., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Significant progress has been made during the past few decades in stem cell therapy research for various diseases and injury states; however this has not been overwhelmingly translated into approved therapies, despite much public attention and the rise in unregulated 'regenerative clinics'. In the last decade, preclinical research focusing on mesenchymal stem/stromal cell (MSC) therapy in experimental animal models of hemorrhagic stroke has gained momentum and has led to the development of a small number of human trials. Here we review the current studies focusing on MSC therapy for hemorrhagic stroke in an effort to summarize the status of preclinical and clinical research. Preliminary evidence indicates that MSCs are both safe and tolerable in patients, however future randomized controlled trials are required to translate the promising preclinical research into an effective therapy for hopeful patients., Competing Interests: The authors declare no competing interests.

Mesenchymal stem cells (MSCs) are becoming an increasingly popular therapeutic option among patients with a broad range of ailments to modulate immunity and induce regeneration. The majority of patients receiving these MSC therapies are on concurrent medication or have ongoing infection. In the present study, we examined the effect of immunosuppressive drugs and lipopolysaccharides (LPS)/endotoxins on the secretory profile, migration towards site of injury, and suppression of lymphocyte proliferation of bone marrow-derived MSCs (BMSCs). Generally, LPS coculture augmented the secretory capacity of BMSCs while exposure to immunosuppressive drugs resulted primarily in no change or attenuated secretion, with some cases of increased secretion, dependent on the cytokine assayed. Among the immunosuppressants evaluated, Hydrocortisone had the most widespread inhibitory effect, while LPS from E. coli O111:B4 had the most potent stimulatory effect. In addition, we also showed that Hydrocortisone or LPS from E. coli O111:B4 affected the migratory and immunosuppressive capacity of BMSCs. Following simulation with Hydrocortisone, BMSC migration was attenuated, and immunosuppressive capacity against T cell proliferation was enhanced, however, the opposite effects were seen with LPS from E. coli O111:B4. Our data suggests that the clinical outcomes of MSC-based therapy are affected by the use of immunosuppressive medication or the presence of endotoxemia in patients., Competing Interests: The authors declare no conflict of interest.

External ventricular drain (EVD) is used clinically to relieve intracranial pressure and occasionally to deliver medications following intracerebral hemorrhage (ICH). Mesenchymal stem cell (MSC) therapy has been shown to be neuroprotective and can induce neuroregeneration in stroke models. We evaluated the safety and efficacy of delivering MSCs intraventricularly in a rat hemorrhagic stroke model. Using autologous blood, hemorrhagic stroke was induced at specific coordinates in the right basal ganglia. After 30 minutes, rats were treated with either bone marrow-derived MSCs or a phosphate-buffered saline placebo via direct intraventricular infusion. Three dosages (2 × 10 5 /kg, 5 × 10 5 /kg, and 1 × 10 6 /kg) of MSCs were administered. Forelimb use asymmetry test was employed to evaluate functional improvement after cell therapy. At the end of the experiment, peripheral blood samples and organs were harvested; biochemistry, cytokine, and growth factor analysis and histology evaluations were performed to explore cell toxicity and cell fate, and the effects of MSC therapy on injury volume, anti-inflammation, and neurogenesis. Intraventricular administration of MSCs in ICH rat model showed improved behavior and alleviated brain damage. Additionally, treated ICH rats showed significantly reduced expression of IL-1α, IL-6, and IFN-γ. No obvious cell toxicity was noticed through blood chemistry and histology evaluation. None of the infused MSCs were detected at the end of the experiment. EVD is safe and effective to use as a method of delivering MSCs to treat ICH. Intraventricularly delivered MSCs have anti-inflammatory properties and a capacity to induce neurogenesis and improve function following ICH injury.

Background: Mobilization regimen choice is a significant contributing factor for successful hematopoietic progenitor cell (HPC) collection by leukocytapheresis and reaching the target CD34+ cell dose. How mobilization regimen affects collection efficiency and the quality of products collected using the Spectra Optia apheresis instrument is not fully known., Methods: We evaluated the impact of granulocyte-colony stimulating factor (GCSF) and GCSF/plerixafor mobilization regimens on CE and product composition. We studied 373 leukocytapheresis HPC collections for 147 autologous transplants from January 1, 2010 to December 31, 2014. Patients were categorized in two groups; good mobilizers, mobilized with GCSF only (GM) and poor mobilizers, mobilized with GCSF and Plerixafor (PM)., Results: Overall, compared with PM group, total nucleated cell (TNC) yield was significantly lower in GM group (P = <.001). In contrast, median percent mononuclear cell (MNC) collected from GM (86.5%) was significantly higher than products collected from PM group (79.5%; P < .001). Compared with GM group, CD34+ cell CE was about 10% lower in PM group (P < .008). In addition, daily CD34+ cell/Kg yield was significantly higher in GM (2.08 × 10/Kg) compared with PM group (1.64 x 10/Kg, P = .019). Overall, the median number of collections per patient was two for GM and three for PM (P = .004)., Conclusion: Products collected from PM group contained higher TNC content relative to GM group but had lower MNC enrichment, CD34+ cell CE and daily CD34+ cell yield per Kg., (© 2018 Wiley Periodicals, Inc.)

Background: Expanding quantities of mesenchymal stem cells (MSCs) sufficient to treat large numbers of patients in cellular therapy and regenerative medicine clinical trials is an ongoing challenge for cell manufacturing facilities., Study Design and Methods: We evaluated options for scaling up large quantities of bone marrow-derived MSCs (BM-MSCs) using methods that can be performed in compliance with Good Manufacturing Practices (GMP). We expanded BM-MSCs from fresh marrow aspirate in αMEM supplemented with 5% human platelet lysate using both an automated cell expansion system (Quantum, Terumo BCT) and a manual flask-based method using multilayer flasks. We compared MSCs expanded using both methods and assessed their differentiation to adipogenic and osteogenic tissue, capacity to suppress T-cell proliferation, cytokines, and growth factor secretion profile and cost-effectiveness of manufacturing enough BM-MSCs to administer a single dose of 100 × 10 6 cells per subject in a clinical trial of 100 subjects., Results: We have established that large quantities of clinical-grade BM-MSCs manufactured with an automated hollow-fiber bioreactor were phenotypically (CD73, CD90, CD105) and functionally (adipogenic and osteogenic differentiation and cytokine and growth factor secretion) similar to manually expanded BM-MSCs. In addition, MSC manufacturing costs significantly less and required less time and effort when using the Quantum automated cell expansion system over the manual multilayer flasks method., Conclusion: MSCs manufactured by an automated bioreactor are physically and functionally equivalent to the MSCs manufactured by the manual flask method and have met the standards required for clinical application., (© 2018 AABB.)

Background: Clinical trials involving mesenchymal stem cell (MSC) therapy have variable outcomes. We hypothesize this is largely attributed to donor-to-donor variability and tissue of origin., Study Design and Methods: We examined proliferation rates, cytokine secretion profiles, and differentiation capability of seven bone marrow-derived MSCs (BM-MSCs) and 16 adipose tissue-derived MSCs (AD-MSCs) from 23 donors., Results: AD-MSCs had the capacity to undergo more than 40 population doublings, while the BM-MSC proliferation rate was found to be considerably slower. We observed more donor-to-donor variability in proliferation rates of BM-MSCs than with AD-MSCs. Cytokine analysis revealed that secretion of eight cytokines was significantly increased by AD-MSCs at Passage (P)3 compared with P1, while for BM-MSCs at P3 relative to P1, only interleukin-8 and RANTES secretion was significantly increased. By P5, secretion of all cytokines by AD-MSCs was either decreased or unchanged relative to P1. In contrast, cytokine secretion by BM-MSCs at P5 was mostly unchanged, although secretion of six cytokines was significantly increased relative to P1. When we compared cytokine secretion between AD-MSCs and BM-MSCs at P3, AD-MSCs significantly secreted higher concentrations of cytokines than BM-MSCs while the opposite was observed at P5. This suggests that BM-MSCs are relatively more potent at P5 while AD-MSCs are relatively more potent at P3. AD-MSCs and BM-MSCs exhibited the capacity for chondrogenic differentiation. AD-MSCs and BM-MSCs appeared to display a more enhanced inclination toward adipogenic and osteogenic differentiation, respectively., Conclusion: MSC physiology is significantly influenced by donor variability and tissue of origin and this should be considered when designing clinical trials., (© 2018 AABB.)

Background: There has been a surge in clinical trials studying the safety and efficacy of mesenchymal stem cells for the treatment of perianal Crohn's disease., Objective: The purpose of this work was to systematically review the literature to determine safety and efficacy of mesenchymal stem cells for the treatment of refractory perianal Crohn's disease., Data Sources: Sources included PubMed, Cochrane Library Central Register of Controlled Trials, and Embase., Study Selection: Studies that reported safety and/or efficacy of mesenchymal stem cells for the treatment of perianal Crohn's disease were included. Two independent assessors reviewed eligible articles., Intervention: The study intervention was delivery of mesenchymal stem cells to treat perianal Crohn's disease., Main Outcomes Measures: Safety and efficacy of mesenchymal stem cells used to treat perianal Crohn's disease were measured., Results: Eleven studies met the inclusion criteria and were included in the systematic review. Three trials with a comparison arm were included in the meta-analysis. There were no significant increases in adverse events (OR = 1.07 (95% CI, 0.61-1.89); p = 0.81) or serious adverse events (OR = 0.53 (95% CI, 0.28-0.98); p = 0.04) in patients treated with mesenchymal stem cells. Mesenchymal stem cells were associated with improved healing as compared with control subjects at primary end points of 6 to 24 weeks (OR = 3.06 (95% CI, 1.05-8.90); p = 0.04) and 24 to 52 weeks (OR = 2.37 (95% CI, 0.90-6.25); p = 0.08)., Limitations: The study was limited by its multiple centers and heterogeneity in the study inclusion criteria, mesenchymal stem cell origin, dose and frequency of delivery, use of scaffolding, and definition and time point of fistula healing., Conclusions: Although there have been only 3 trials conducted with control arms, existing data demonstrate improved efficacy and no increase in adverse or serious adverse events with mesenchymal stem cells as compared with control subjects for the treatment of perianal Crohn's disease.

Feasibility, tolerance, and safety of intravenous infusions of allogeneic mesenchymal stem cell (MSC) therapy in lung transplant recipients with bronchiolitis obliterans syndrome (BOS) are not well established. MSCs were manufactured, cryopreserved, transported to our facility, thawed, and infused into nine recipients with moderate BOS (average drop in forced expiratory volume in 1 second was 56.8% ± 3.2% from post-transplant peak) who were refractory to standard therapy and not candidates for retransplant. Cells were viable and sterile prior to infusion. Patients received a single infusion of either 1 (n = 3), 2 (n = 3), or 4 (n = 3) million MSCs per kg. Patients were medically evaluated before; during; and at 24 hours, 1 week, and 1 month after infusion for evidence of infusion-related adverse events and tolerance of therapy. Vital signs, pulmonary function test results, Borg Dyspnea Index, and routine laboratory data were recorded. Vital signs and O 2 saturation did not significantly change during or up to 2 hours after MSC infusion. There were no significant changes in gas exchange variables, pulmonary function test results, or laboratory values at 1, 7, and 30 days postinfusion compared with preinfusion values. Infusion of MSCs in patients with BOS was feasible, safe, and well tolerated and did not produce any significant adverse changes in clinical, functional, or laboratory variables during or up to 30 days after infusion. Manufacturing, transport, and administration of intravenous, allogeneic bone marrow-derived MSCs in doses from 1 to 4 million MSCs per kg is safe in lung transplant recipients with BOS. Stem Cells Translational Medicine 2018;7:161-167., (© 2018 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Background: Bone marrow aspirate concentrate (BMAC) is increasingly used as a regenerative therapy for musculoskeletal pathological conditions despite limited evidence-based support., Hypothesis: BMAC will prove feasible, safe, and efficacious for the treatment of pain due to mild to moderate degenerative joint disease of the knee., Study Design: Randomized controlled trial; Level of evidence, 2., Methods: In this prospective, single-blind, placebo-controlled trial, 25 patients with bilateral knee pain from bilateral osteoarthritis were randomized to receive BMAC into one knee and saline placebo into the other. Fifty-two milliliters of bone marrow was aspirated from the iliac crests and concentrated in an automated centrifuge. The resulting BMAC was combined with platelet-poor plasma for an injection into the arthritic knee and was compared with a saline injection into the contralateral knee, thereby utilizing each patient as his or her own control. Safety outcomes, pain relief, and function as measured by Osteoarthritis Research Society International (OARSI) measures and the visual analog scale (VAS) score were tracked initially at 1 week, 3 months, and 6 months after the procedure., Results: There were no serious adverse events from the BMAC procedure. OARSI Intermittent and Constant Osteoarthritis Pain and VAS pain scores in both knees decreased significantly from baseline at 1 week, 3 months, and 6 months ( P ≤ .019 for all). Pain relief, although dramatic, did not differ significantly between treated knees ( P > .09 for all)., Conclusion: Early results show that BMAC is safe to use and is a reliable and viable cellular product. Study patients experienced a similar relief of pain in both BMAC- and saline-treated arthritic knees. Further study is required to determine the mechanisms of action, duration of efficacy, optimal frequency of treatments, and regenerative potential. Registration: ClinicalTrials.gov record 12-004459.

Background Aims: Aberrant production of reactive oxygen species (ROS) and its impact on the integrity of genomic DNA have been considered one of the major risk factors for the loss of dopaminergic neurons in Parkinson's disease (PD). Stem cell transplantation as a strategy to replenish new functional neurons has great potential for PD treatment. However, limited survival of stem cells post-transplantation has always been an obstacle ascribed to the existence of neurotoxic environment in PD patients., Methods: To improve the survival of transplanted stem cells for PD treatment, we explored a new strategy based on the function of the H2AX gene (H2A histone family, member X) in determination of DNA repair and cell apoptosis. We introduced a mutant form Y142F of H2AX into dopamine (DA) neuron-like cells differentiated from bone marrow-derived mesenchymal stromal cells (BMSCs)., Results: Expression of H2AX(Y142F) renders DA neuron-like cells more resistant to DNA damage and subsequent cell death induced by ultraviolet irradiation and 1-methyl-4-phenylpyridinium (MPP+) treatment., Discussion: This is a meaningful attempt to improve the sustainability of BMSC-derived dopamine neurons under a brain neurotoxic environment. Further studies are needed to evaluate the implications of our findings in stem cell therapy for PD and related diseases., (Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)