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The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (KO) (Gpr109a−/−) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared with recipients of wild-type (WT) T cells. Recipients of Gpr109a−/− T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a−/− T cells did not exhibit immune deficits at a steady state, following allo-activation, Gpr109a−/− T cells underwent increased apoptosis and were impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetylcysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.

Adult stem cells like mammary and mesenchymal stem cells have received significant attention because these stem cells possess therapeutic potential in treating many animal diseases. These cells can be administered in an autologous or allogenic fashion, either freshly isolated from the donor tissue or previously cultured and expanded in vitro. The expansion of adult stem cells is a prerequisite before therapeutic application because sufficient numbers are required in dosage calculation. Stem cells directly and indirectly (by secreting various growth factors and angiogenic factors called secretome) act to repair and regenerate injured tissues. Recent studies on mammary stem cells showed in vivo and in vitro expansion ability by removing the blockage of asymmetrical cell division. Compounds like purine analogs (xanthosine, xanthine, and inosine) or hormones (progesterone and bST) help increase stem cell population by promoting cell division. Such methodology of enhancing stem cell number, either in vivo or in vitro, may help in preclinical studies for translational research like treating diseases such as mastitis. The application of mesenchymal stem cells has also been shown to benefit mammary gland health due to the ‘homing’ property of stem cells. In addition to that, the multiple positive effects of stem cell secretome are on mammary tissue; healing and killing bacteria is novel in the production of quality milk. This systematic review discusses some of the studies on stem cells that have been useful in increasing the stem cell population and increasing mammary stem/progenitor cells. Finally, we provide insights into how enhancing mammary stem cell population could potentially increase terminally differentiated cells, ultimately leading to more milk production.

Although multifarious tumor-targeting modifications of nanoparticulate systems have been attempted in joint efforts by our predecessors, it remains challenging for nanomedicine to traverse physiological barriers involving blood vessels, tissues, and cell barriers to thereafter demonstrate excellent antitumor effects. To further overcome these inherent obstacles, we designed and prepared mycoplasma membrane (MM)-fused liposomes (LPs) with the goal of employing circulating neutrophils with the advantage of inflammatory cytokine-guided autonomous tumor localization to transport nanoparticles. We also utilized in vivo neutrophil activation induced by the liposomal form of the immune activator resiquimod (LPs-R848). Fused LPs preparations retained mycoplasma pathogen characteristics and achieved rapid recognition and endocytosis by activated neutrophils stimulated by LPs-R848. The enhanced neutrophil infiltration in homing of the inflammatory tumor microenvironment allowed more nanoparticles to be delivered into solid tumors. Facilitated by the formation of neutrophil extracellular traps (NETs), podophyllotoxin (POD)-loaded MM-fused LPs (MM-LPs-POD) were concomitantly released from neutrophils and subsequently engulfed by tumor cells during inflammation. MM-LPs-POD displayed superior suppression efficacy of tumor growth and lung metastasis in a 4T1 breast tumor model. Overall, such a strategy of pathogen-mimicking nanoparticles hijacking neutrophils in situ combined with enhanced neutrophil infiltration indeed elevates the potential of chemotherapeutics for tumor targeting therapy.

Few studies have investigated immune cell ontogeny throughout the neonatal and early pediatric period, when there is often increased vulnerability to infections. In this study, we evaluated the dynamics of two critical T cell populations, T regulatory (Treg) cells and Th17 cells, over the first 36 wk of human life. First, we observed distinct CD4+ T cells phenotypes between cord blood and peripheral blood, collected within 12 h of birth, showing that cord blood is not a surrogate for newborn blood. Second, both Treg and Th17 cells expanded in a synchronous fashion over 36 wk of life. However, comparing infants exposed to HIV in utero, but remaining uninfected, with HIV-unexposed uninfected control infants, there was a lower frequency of peripheral blood Treg cells at birth, resulting in a delayed expansion, and then declining again at 36 wk. Focusing on birth events, we found that Treg cells coexpressing CCR4 and α4β7 inversely correlated with plasma concentrations of CCL17 (the ligand for CCR4) and intestinal fatty acid binding protein, IL-7, and CCL20. This was in contrast with Th17 cells, which showed a positive association with these plasma analytes. Thus, despite the stereotypic expansion of both cell subsets over the first few months of life, there was a disruption in the balance of Th17 to Treg cells at birth likely being a result of gut damage and homing of newborn Treg cells from the blood circulation to the gut.

Bones are the functional tissue, to provide structural support, protect vital organs, store minerals, helps in multi-directional motion and bear load of our body. Fracture of bones, in which continuity of bone tissue breaks, which occurred due to trauma (high intensity impact) and over stressing are treated with help of bone implants. Bone implants are fabricated through biomaterials which are categorized as as: (a) first generation, (b) second generation and (c) third generation biomaterials. First generation implants are bioinert, second generation implants are biodegradable, bioinert and bioactive. Third generation implants focuses on stimulating specific cellular response at molecular level along with the properties of second generation. Bone tissue engineering (BTE) is responsive for the evolution of third generation implants, where the main focus is to create the environment which helps to stimulate the cell response in direction of bone regeneration. This aim is achieved with engineered tissue implant which includes: (a) scaffold for architectural support & cell homing, (b) osteogenic cells and (c) signaling growth factors. Tissues in human body are the 3D repeating unit cells also called as extra cellular matrix (ECM). Similarly scaffold is the artificial 3D porous structure of biomaterials (ceramics, metals and polymers) which mimic those 3D repeating unit cells or ECM. Scaffold is a backbone or fundamental unit of BTE. Success of scaffold decides the success of engineered bone tissue implant. This review summarizes the factor influencing BTE, factor involved in selection of material for scaffold fabrication and trending fabrication methods for BTE scaffolds.

T and B cells employ integrin α4β7 to migrate to intestine under homeostatic conditions. Whether those cells differentially rely on α4β7 for homing during inflammatory conditions has not been fully examined. This may have implications for our understanding of the mode of action of anti-integrin therapies in inflammatory bowel disease (IBD). Here, we examined the role of α4β7 integrin during chronic colitis using IL-10−/− mice, β7-deficient IL-10−/−, IgA-deficient IL-10−/− mice, and antibody blockade of MAdCAM-1. We found that α4β7 was predominantly expressed by B cells. β7 deficiency and MAdCAM-1 blockade specifically depleted antibody secreting cells (ASC) (not T cells) from the colonic LP, leading to a fecal pan-immunoglobulin deficit, severe colitis, and alterations of microbiota composition. Colitis was not due to defective regulation, as dendritic cells (DC), regulatory T cells, retinaldehyde dehydrogenase (RALDH) expression, activity, and regulatory T/B-cell cytokines were all comparable between the strains/treatment. Finally, an IgA deficit closely recapitulated the clinical phenotype and altered microbiota composition of β7-deficient IL-10−/− mice. Thus, a luminal IgA deficit contributes to accelerated colitis in the β7-deficient state. Given the critical/nonredundant dependence of IgA ASC on α4β7:MAdCAM-1 for intestinal homing, B cells may represent unappreciated targets of anti-integrin therapies.

This paper proposes a novel guidance law based on model predictive control for protecting an aircraft from a homing missile. Considering that in the target‐missile‐defender engagement the attacking missile is pursuing the target aircraft by employing a known linear guidance law, a non‐linear predictive model for the engagement is established. This predictive model allows converting the three‐body engagement to a one‐on‐one engagement. The time‐to‐go for the defender towards the future position of the incoming missile is analytically derived, indicating that the optimal time for the defender to intercept the incoming missile is a fixed‐point of a real‐valued function. As a result, the optimal interception duration can be obtained by a standard fixed‐point iteration method, and thus the interception point can be readily predicted via integrating the predictive model. The guidance command is generated by directly leading the defender to the predicted intercept point. Numerical simulations in different scenarios validate the algorithm to be computationally efficient, and demonstrate that the proposed strategy outperforms previous techniques in terms of miss distance, engagement duration, and the control effort.

Summary Mesenchymal stromal cells (MSCs) have shown significant heterogeneity in terms of therapeutic efficacy for inflammatory bowel disease (IBD) treatment, which may be due to an insufficient number of MSCs homing to the damaged tissue of the colon. Engineering MSCs with specific chemokine receptors can enhance the homing ability by lentiviral transduction. However, the unclear specific chemokine profile related to IBD and the safety concerns of viral-based gene delivery limit its application. Thus, a new strategy to modify MSCs to express specific chemokine receptors using mRNA engineering is developed to evaluate the homing ability of MSCs and its therapeutic effects for IBD. We found that CXCL2 and CXCL5 were highly expressed in the inflammatory colon, while MSCs minimally expressed the corresponding receptor CXCR2. Transient expression of CXCR2 in MSC was constructed and exhibited significantly enhanced migration to the inflamed colons, leading to a robust anti-inflammatory effect and high efficacy. Furthermore, the high expression of semaphorins7A on MSCs were found to induce the macrophages to produce IL-10, which may play a critical therapeutic role. This study demonstrated that the specific chemokine receptor CXCR2 mRNA-engineered MSCs not only improves the therapeutic efficacy of IBD but also provides an efficient and safe MSC modification strategy., Graphical abstract, Li et al. demonstrate that mRNA-engineered MSCs with CXCR2 significantly increase their migratory properties to injured organ/tissue in an inflammatory bowel mouse model. This strategy for enhancing targeted stem/progenitor cell homing may provide a potential strategy to improve the efficacy of MSC-based therapeutics and be applicable to clinical patients.

Tumor-draining lymph nodes (TDLNs) are the primary sites to initiate immune responses against cancer, as well as the origin of metastasis for most breast cancer cases. Reverting the immunosuppression microenvironment in TDLNs is critical to improving the outcome of the malignancy, though still a big technical challenge. In this study, a type of smart exosomes was developed in which the exosome surface was functionally engineered with CD62L (L-selectin, a gene for lymphocyte homing to lymph nodes) and OX40L (CD134L, a gene for effector T cell expansion and regulatory T cell [Treg] inhibition) by forced expression of the genes in the donor cells. Compared with control exosomes, the smart exosomes displayed strong TDLN homing capacity in the 4T1 syngeneic mouse model. Moreover, injection of the smart exosomes activated effector T cells and inhibited Treg induction, thereby amplifying the antitumor immune response and inhibiting tumor development. Together, the engineered smart exosomes provide a novel nanoplatform for TDLN-targeted delivery and cancer immunotherapy., Graphical abstract, Ji et al. here have engineered a kind of smart exosomes with CD62L and OX40L displayed on the surface. The engineered exosomes have strong lymph node homing capacity and revert the immunosuppression microenvironment in tumor-draining lymph nodes, holding promise for cancer immunotherapy.

Endothelial progenitor cells (EPCs) promote angiogenesis and play an important role in myocardial and vascular repair after ischemia and infarction. EPCs consist of different subpopulations including CD34‑CD133+ EPCs, which are precursors of more mature CD34+CD133+ EPCs and functionally more active in terms of homing and endothelial regeneration. In the present study we analyzed the functional and differentiation abilities of CD34‑CD133+ EPCs. Isolation of EPC populations (CD34+CD133+, CD34‑CD133+) were performed by specific multi‑step magnetic depletion. After specific stimulation a significant higher adhesive and migrative capacity of CD34‑CD133+ cells could be detected compared to CD34+CD133+ cells (P

Memory T (TM) cells play an important role in the long-term defense against pathogen reinvasion. However, it is still unclear how these cells receive the crucial signals necessary for their longevity and homeostatic turnover. To understand how TM cells receive these signals, we infected mice with lymphocytic choriomeningitis virus (LCMV) and examined the expression sites of neural cadherin (N-cadherin) by immunofluorescence microscopy. We found that N-cadherin was expressed in the surroundings of the white pulps of the spleen and medulla of lymph nodes (LNs). Moreover, TM cells expressing high levels of killer cell lectin-like receptor G1 (KLRG1), a ligand of N-cadherin, were co-localized with N-cadherin+ cells in the spleen but not in LNs. We then blocked N-cadherin in vivo to investigate whether it regulates the formation or function of TM cells. The numbers of CD127hiCD62Lhi TM cells in the spleen of memory P14 chimeric mice declined when N-cadherin was blocked during the contraction phase, without functional impairment of these cells. In addition, when CD127loKLRG1hi TM cells were adoptively transferred into anti–N-cadherin–treated mice compared with control mice, the number of these cells was reduced in the bone marrow and LNs, without functional loss. Taken together, our results suggest that N-cadherin participates in the development of CD127hiCD62Lhi TM cells and homing of CD127loKLRG1hi TM cells to lymphoid organs.

Autoimmunity in Lewy body dementia Lewy body dementia (LBD) is a brain disease that leads to progressive decline in thinking, movement, and independent function. It results from the build-up of microscopic deposits called Lewy bodies, which develop from the aggregation of a misfolded protein called α-synuclein. Gate et al . observed immune cells known as T cells in the brains of LBD patients (see the Perspective by Krot and Rolls). Genomics analysis revealed that T cells traffic to the LBD brain and are associated with neuronal damage. When stimulated with α-synuclein, LBD patient T cells secrete an inflammatory protein known to damage neurons. These findings suggest an unexpected detrimental role of the immune system in LBD. —SMH

Background & Aims Thymic conventional dendritic cells (t‑DCs) are crucial for the development of T cells. A substantial fraction of t‑DCs originates extrathymically and migrates to the thymus. Here, these cells contribute to key processes of central tolerance like the clonal deletion of self‑reactive thymocytes and the generation of regulatory T (Treg) cells. So far, it is only incompletely understood which impact the thymic microenvironment has on thymus‑homing conventional DCs (cDCs), which phenotypic changes occur after the entry of peripheral cDCs into the thymus and which functional properties these modulated cells acquire. Materials & Methods In the present study, we mimicked the thymus‑homing of peripheral cDCs by introducing ex vivo isolated splenic cDCs (sp‑DCs) into reaggregated thymic organ cultures (RTOCs). Results Already after two days of culture, the transcriptomic profile of sp‑DCs was modulated and had acquired certain key signatures of t‑DCs. The regulated genes included immunomodulatory cytokines and chemokines as well as costimulatory molecules. After four days of culture, sp‑DCs appeared to have at least partially acquired the peculiar Treg cell‐inducing capacity characteristic of t‑DCs. Discussion & Conclusion Taken together, our findings indicate that peripheral cDCs possess a high degree of plasticity enabling them to quickly adapt to the thymus‐specific microenvironment. We further provide indirect evidence that thymus‐specific properties such as the efficient induction of Treg cells under homeostatic conditions can be partially transferred to thymus‑homing peripheral cDC subsets., Thymic conventional dendritic cells (t‐DCs) are crucial for the development of T cells and central tolerance. A substantial fraction of t‐DCs originates extrathymically and migrates to the thymus. Here, we used reaggregated thymic organ cultures (RTOCs) to demonstrate that these thymus‐homing DCs are plastic and can acquire essential thymus‐specific properties upon entry into the thymus.

Background: Hematopoietic stem cell (HSC) transplantation is considered a possible treatment option capable of curing various diseases. The aim of this study was the co-culturing of mesenchymal stem cell (MSC) spheres with HSCs under hypoxic condition to enhance the proliferation, self-renewal, stemness, and homing capacities of HSCs.Methods and results: HSCs were expanded after being subjected to different conditions including cytokines without feeder (Cyto), co-culturing with adherent MSCs (MSC), co-culturing with adherent MSCs+ hypoxia (MSC+ Hyp), co-culturing with MSCs spheres (Sph-MSC), co-culturing with MSCs spheres+ hypoxia (Sph-MSC+ Hyp), co-culturing with MSC spheres+ cytokines (Sph-MSC+Cyto). After 10 days, total nucleated cell (TNC) and CD34+/CD38- cell counts, colony-forming unit assay (CFU), long-term culture initiating cell (LTC-IC), the expression of endothelial protein C receptor (EPCR), nucleostemin (NS), nuclear factor I/X (Nfix) CXCR4, and VLA-4 were evaluated. The TNC, CD34+/CD38- cell count, CFU, and LTC-IC were higher in the Sph-MSC+ Hyp and Sph-MSC+ Cyto groups as compared with those of the MSC+ Hyp group (PConclusion: Co-culturing HSCs with MSC spheres under hypoxic condition not only leads to higher cellular yield but also increases the expression of self-renewal and homing genes. Therefore, we suggest this approach as a simple and non-expensive strategy that might improve the transplantation efficiency of HSCs.

Background Intimal hyperplasia caused by vascular injury is an important pathological process of many vascular diseases, especially occlusive vascular disease. In recent years, Nano-drug delivery system has attracted a wide attention as a novel treatment strategy, but there are still some challenges such as high clearance rate and insufficient targeting. Results In this study, we report a biomimetic ROS-responsive MM@PCM/RAP nanoparticle coated with macrophage membrane. The macrophage membrane with the innate “homing” capacity can superiorly regulate the recruitment of MM@PCM/RAP to inflammatory lesion to enhance target efficacy, and can also disguise MM@PCM/RAP nanoparticle as the autologous cell to avoid clearance by the immune system. In addition, MM@PCM/RAP can effectively improve the solubility of rapamycin and respond to the high concentration level of ROS accumulated in pathological lesion for controlling local cargo release, thereby increasing drug availability and reducing toxic side effects. Conclusions Our findings validate that the rational design, biomimetic nanoparticles MM@PCM/RAP, can effectively inhibit the pathological process of intimal injury with excellent biocompatibility. Graphical Abstract

Endothelial cells play a critical role in supporting postnatal hematopoiesis in the bone marrow. Unique endothelial cells, together with various perivascular cells, form different types of vascular structures, constructing a vast microvascular delivery and trafficking network for blood cells, oxygen, and nutrition. These blood vessels build distinct hematopoietic stem and progenitor cell niches, which offer not only sites of residence for blood cells but also indispensable signals directing HSPC homing, self-renewal, and multilineage differentiation. Deep insight into the structure and function of the BM vasculature niche and its participation in hematopoiesis is necessary to develop advanced strategies for the reconstitution of hematopoiesis.

Tumor metastasis is the leading cause of cancer mortality, often characterized by abnormal cell growth and invasion to distant organs. The cancer invasion due to epithelial to mesenchymal transition is affected by metabolic and oxygen availability in the tumor-associated micro-environment. A precise alteration in oxygen and metabolic signaling between healthy and metastatic cells is a substantial probe for understanding tumor progression and metastasis. Molecular heterogeneity in the tumor microenvironment help to sustain the metastatic cell growth during their survival shift from low to high metabolic-oxygen-rich sites and reinforces the metastatic events. This review highlighted the crucial role of oxygen and metabolites in metastatic progression and exemplified the role of metabolic rewiring and oxygen availability in cancer cell adaptation. Furthermore, we have also addressed potential applications of altered oxygen and metabolic networking with tumor type that could be a signature pattern to assess tumor growth and chemotherapeutics efficacy in managing cancer metastasis.

Metastasis is the leading cause of cancer-related deaths, and metastatic cancers remain largely incurable due to chemoresistance. Biomarkers of metastatic cells are lacking, and probes that could be used to detect and target metastases would be highly valuable. Here we hypothesize that metastatic cancer cells express cell-surface receptors that can be harnessed for identification of molecules homing to metastases. Screening a combinatorial library in a mouse mammary tumor model of spontaneous metastasis identified cyclic peptides with tropism for cancer cells disseminated to the lungs. Two lead peptides, CLRHSSKIC and CRAGVGRGC, bound murine and human cells derived from breast carcinoma and melanoma in culture and were selective for metastatic cells in vivo. In mice, peptide CRAGVGRGC radiolabeled with 67Ga for biodistribution analysis demonstrated selective probe homing to lung metastases. Moreover, systemic administration of 68Ga-labeled CRAGVGRGC enabled noninvasive imaging of lung metastases in mice by PET. A CRAGVGRGC-derived peptide induced apoptosis upon cell internalization in vitro and suppressed metastatic burden in vivo. Colocalization of CLRHSSKIC and CRAGVGRGC with N-cadherin+/E-cadherin− cells indicated that both peptides are selective for cancer cells that have undergone the epithelial-to-mesenchymal transition. We conclude that CRAGVGRGC is useful as a probe to facilitate the development of imaging modalities and therapies targeting metastases. Significance: This study identifies new molecules that bind metastatic cells and demonstrates their application as noninvasive imaging probes and vehicles for cytotoxic therapy delivery in preclinical cancer models.

The two major challenges in cancer treatment include lack of early detection and ineffective therapies with various side effects. Angiogenesis is the key process in the growth, survival, invasiveness, and metastasis of many of cancerous tumors. Imaging of the angiogenesis could lead to diagnosis of tumors in the early stage and evaluation of the therapeutic responses. Angiogenic blood vessels express specific molecular markers different from normal blood vessels (in level or kind). This fact would make the tumor vasculature a suitable site to target therapeutics and imaging agents within the tumor. Surface modified nanoparticles using peptide ligands with high binding affinity to the vasculature markers, provide efficient delivery of therapeutic and imaging agents, while avoiding undesirable side effects. In this review, we discuss discoveries of various tumor targeting peptides useful for tumor angiogenesis imaging and targeted therapy with emphasis on surface modified nanomedicines using vasculature targeting peptides.

Although root canal therapy is the most common and widely used treatment at clinical presentation, there are still some postoperative complications. As cell biology and tissue engineering techniques advance rapidly, the use of biological therapy to regenerate dental pulp has become a new trend; Relevant literatures in recent five years were searched using key words such as “root canal therapy”, “Dental pulp stem cells”, “Dental pulp regeneration”, and “Cell homing” in PubMed, Web of Science, etc; Dental pulp stem cells (DPSCs) have multi-differentiation potential, self-renewal capability, and high proliferative ability. Stem cell-based dental pulp regeneration has emerged as a new research hot spot in clinical therapy. Recently, dental pulp-like structures have been generated by the transplantation of exogenous DPSCs or the induction of homing of endogenous DPSCs. Studies on DPSCs are important and significant for dental pulp regeneration and dental restoration; In this review, the existing clinical treatment methods, dental pulp regeneration, and DPSC research status are revealed, and their application prospects are discussed. The stem cell-based pulp regeneration exerts promising potential in clinical therapy for pulp regeneration.

A novel hybridized dual-targeting peptide-based nanoprobe was successfully designed by using the cyclic heptapeptide. This peptide has Arg-Gly-Asp-Lys-Leu-Ala-Lys sequence, in which the RGD homing motif and KALK mitochondria-targeting motif were linked via amide bond. The designed peptide probe was further modified through covalent linkage to induce dual-imaging functionality, and self-assembled to form spherical nanoparticles. The novel Cy5.5-SAPD-99mTc nanoparticles were tested for in vitro cytotoxicity, cellular uptake, and apoptosis-inducing functionalities. The cellular internalization, enhanced cytotoxicity and selective receptor binding capabilities against U87MG cells, excellent dual-imaging potential, improved apoptosis-inducing feature by damaging mitochondria, and in vivo preclinical investigations suggested that our newly designed novel hybridized peptide-based dual-imaging nanoparticles may serve as an admirable theranostic probe to treat brain tumor glioblastoma multiforme. This study describes the development of dual-targeting self-assembled peptide nanoparticles followed by modifications using NIRF dye and radiolabeled with 99mTc for dual-imaging and enhanced therapeutic efficacy against brain tumor.

We show that pro-inflammatory oncostatin M (OSM) is an important regulator of hematopoietic stem cell (HSC) niches in the bone marrow (BM). Treatment of healthy humans and mice with granulocyte colony-stimulating factor (G-CSF) dramatically increases OSM release in blood and BM. Using mice null for the OSM receptor (OSMR) gene, we demonstrate that OSM provides a negative feed-back acting as a brake on HSPC mobilization in response to clinically relevant mobilizing molecules G-CSF and CXCR4 antagonist. Likewise, injection of a recombinant OSM molecular trap made of OSMR complex extracellular domains enhances HSC mobilization in poor mobilizing C57BL/6 and NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. Mechanistically, OSM attenuates HSC chemotactic response to CXCL12 and increases HSC homing to the BM signaling indirectly via BM endothelial and mesenchymal cells which are the only cells expressing OSMR in the BM. OSM up-regulates E-selectin expression on BM endothelial cells indirectly increasing HSC proliferation. RNA sequencing of HSCs from Osmr-/- and wild-type mice suggest that HSCs have altered cytoskeleton reorganization, energy usage and cycling in the absence of OSM signaling in niches. Therefore OSM is an important regulator of HSC niche function restraining HSC mobilization and anti-OSM therapy combined with current mobilizing regimens may improve HSPC mobilization for transplantation.

Mesenchymal stem cell (MSC) transplantation is regarded as a promising candidate for the treatment of ischaemic heart disease. The major hurdles for successful clinical translation of MSC therapy are poor survival, retention, and engraftment in the infarcted heart. Stromal cell-derived factor-1/chemokine receptor 4 (SDF-1/CXCR4) constitutes one of the most efficient chemokine/chemokine receptor pairs regarding cell homing. In this review, we mainly focused on previous studies on how to regulate the SDF-1/CXCR4 interaction through various priming strategies to maximize the efficacy of mesenchymal stem cell transplantation on ischaemic hearts or to facilitate the required effects. The strengthened measures for enhancing the therapeutic efficacy of the SDF-1/CXCR4 interaction for mesenchymal stem cell transplantation included the combination of chemokines and cytokines, hormones and drugs, biomaterials, gene engineering, and hypoxia. The priming strategies on recipients for stem cell transplantation included ischaemic conditioning and device techniques.

Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) have been studied for their application to manage various neurological diseases, owing to their anti-inflammatory, immunomodulatory, paracrine, and antiapoptotic ability, as well as their homing capacity to specific regions of brain injury. Among mesenchymal stem cells, such as BM-MSCs, adipose-derived MSCs, and umbilical cord MSCs, BM-MSCs have many merits as cell therapeutic agents based on their widespread availability and relatively easy attainability and in vitro handling. For stem cell-based therapy with BM-MSCs, it is essential to perform ex vivo expansion as low numbers of MSCs are obtained in bone marrow aspirates. Depending on timing, before hBM-MSC transplantation into patients, after detaching them from the culture dish, cell viability, deformability, cell size, and membrane fluidity are decreased, whereas reactive oxygen species generation, lipid peroxidation, and cytosolic vacuoles are increased. Thus, the quality and freshness of hBM-MSCs decrease over time after detachment from the culture dish. Especially, for neurological disease cell therapy, the deformability of BM-MSCs is particularly important in the brain for the development of microvessels. As studies on the traditional characteristics of hBM-MSCs before transplantation into the brain are very limited, omics and machine learning approaches are needed to evaluate cell conditions with indepth and comprehensive analyses. Here, we provide an overview of hBM-MSCs, the application of these cells to various neurological diseases, and improvements in their quality and freshness based on integrated omics after detachment from the culture dish for successful cell therapy.

Chronic granulomatous disease (CGD) is an inherited blood disorder of phagocytic cells that renders patients susceptible to infections and inflammation. A recent clinical trial of lentiviral gene therapy for the most frequent form of CGD, X-linked, has demonstrated stable correction over time, with no adverse events related to the gene therapy procedure. We have recently developed a parallel lentiviral vector for p47phox-deficient CGD (p47phoxCGD), the second most common form of this disease. Using this vector, we have observed biochemical correction of CGD in a mouse model of the disease. In preparation for clinical trial approval, we have performed standardized preclinical studies following Good Laboratory Practice (GLP) principles, to assess the safety of the gene therapy procedure. We report no evidence of adverse events, including mutagenesis and tumorigenesis, in human hematopoietic stem cells transduced with the lentiviral vector. Biodistribution studies of transduced human CD34+ cells indicate that the homing properties or engraftment ability of the stem cells is not negatively affected. CD34+ cells derived from a p47phoxCGD patient were subjected to an optimized transduction protocol and transplanted into immunocompromised mice. After the procedure, patient-derived neutrophils resumed their function, suggesting that gene correction was successful. These studies pave the way to a first-in-man clinical trial of lentiviral gene therapy for the treatment of p47phoxCGD.

The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome (NS), a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular, and nervous systems. Consistent with the abnormalities seen in NS, a host of new studies have implicated R-Ras proteins in physiological and pathologic changes in cellular morphology, adhesion, and migration in the cardiovascular, immune, and nervous systems. These changes include regulating the migration and homing of mature and immature immune cells, vascular stabilization, clotting, and axonal and dendritic outgrowth during nervous system development. Dysregulated R-Ras signaling has also been linked to the pathogenesis of cardiovascular disease, intellectual disabilities, and human cancers. This review discusses the structure and regulation of R-Ras proteins and our current understanding of the signaling pathways that they regulate. It explores the phenotype of NS patients and their implications for the R-Ras subfamily functions. Next, it covers recent discoveries regarding physiological and pathologic R-Ras functions in key organ systems. Finally, it discusses how R-Ras signaling is dysregulated in cancers and mechanisms by which this may promote neoplasia.

ObjectiveThe anti-α4β7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab.DesignWe characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4β7 integrin-expressing T cell populations ‘resistant’ to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies.ResultsRegulatory T (TReg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (TEff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4β7 on TReg cells in vivo was higher than that of/on TEff cells. We identified a vedolizumab-‘resistant’ α4β7-expressing β1+PI16+ TReg cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials.ConclusionCompletely blocking TEff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful TReg cells in an optimal ‘therapeutic window’ based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.

Endothelial progenitor cells (EPCs) are immature endothelial cells that participate in vascular repair and postnatal neovascularization and provide a novel and promising therapy for the treatment of vascular disease. Studies in different animal models have shown that EPC mobilization through pharmacological agents and autologous EPC transplantation contribute to restoring blood supply and tissue regeneration after ischemic injury. However, these effects of the progenitor cells in clinical studies exhibit mixed results. The therapeutic efficacy of EPCs is closely associated with the number of the progenitor cells recruited into ischemic regions and their functional abilities and survival in injury tissues. In this review, we discussed the regulating role of stromal cell-derived factor-1 (also known CXCL12, SDF-1) in EPC mobilization, recruitment, homing, vascular repair and neovascularization, and analyzed the underlying machemisms of these functions. Application of SDF-1 to improve the regenerative function of EPCs following vascular injury was also discussed. SDF-1 plays a crucial role in mobilizing EPC from bone marrow into peripheral circulation, recruiting the progenitor cells to target tissue and protecting against cell death under pathological conditions; thus improve EPC regenerative capacity. SDF-1 are crucial for regulating EPC regenerative function, and provide a potential target for improve therapeutic efficacy of the progenitor cells in treatment of vascular disease.

How hematopoietic stem cells (HSCs) coordinate their divisional axis and whether this orientation is important for stem cell–driven hematopoiesis is poorly understood. Single-cell RNA sequencing data from patients with Shwachman-Diamond syndrome (SDS), an inherited bone marrow failure syndrome, show that ARHGEF2, a RhoA-specific guanine nucleotide exchange factor and determinant of mitotic spindle orientation, is specifically downregulated in SDS hematopoietic stem and progenitor cells (HSPCs). We demonstrate that transplanted Arhgef2−/− fetal liver and bone marrow cells yield impaired hematopoietic recovery and a production deficit from long-term HSCs, phenotypes that are not the result of differences in numbers of transplanted HSCs, their cell cycle status, level of apoptosis, progenitor output, or homing ability. Notably, these defects are functionally restored in vivo by overexpression of ARHGEF2 or its downstream activated RHOA GTPase. By using live imaging of dividing HSPCs, we show an increased frequency of misoriented divisions in the absence of Arhgef2. ARHGEF2 knockdown in human HSCs also impairs their ability to regenerate hematopoiesis, culminating in significantly smaller xenografts. Together, these data demonstrate a conserved role for Arhgef2 in orienting HSPC division and suggest that HSCs may divide in certain orientations to establish hematopoiesis, the loss of which could contribute to HSC dysfunction in bone marrow failure.

Objectives Chemokines (CKs) are key players of immune-cell homing and differentiation. CK receptors (CKRs) can be used to define T-cell functional subsets. We aimed to characterize the CKR profile of the regulatory B-cell subset B10+ cells and investigate the CKs involved in their migration and differentiation in healthy donors and patients with RA. Methods RNA sequencing and cytometry were used to compare CKR expression between B10+ and B10neg cells. Migration of B10+ and B10neg cells and IL-10 secretion of B cells in response to recombinant CKs or synovial fluid (SF) were assessed. Results CXCR5 was expressed at a higher level on the B10+ cell surface as compared with other B cells (referred to as B10neg cells). In line with this, its ligand CXCL13 preferentially attracted B10+ cells over B10neg cells. Interestingly, synovial fluid from RA patients contained high levels of CXCL13 and induced strong and preferential migration of B10+ cells. Besides its role in attracting B10+ cells, CXCL13 also promoted IL-10 secretion by B cells. In RA patients, the level of CXCR5 on B-cell surface was reduced. The preferential migration of RA B10+ cells toward CXCL13-rich SF was lost and CXCL13 stimulation triggered less IL-10 secretion than in healthy donors. Conclusion Our results identify that the CXCR5/CXCL13 axis is essential for B10+ cell biology but is defective in RA. Restoring the preferential migration of B10+ within the affected joints to better control inflammation may be part of the therapeutic approach for RA.

This article proposes a novel homing behavior model of pigeons and the simulation results are presented. A homing pigeon-inspired autonomous navigation system for an unmanned aerial vehicle (UAV) is further achieved. Experimental results on the designed simulation platform show that UAV can finish an autonomous return voyage similar to the homing pigeon.

Cellular therapy exerts profound therapeutic potential for curing a broad spectrum of diseases. Adult stem cells reside within a specified dynamic niche in vivo, which is essential for continuous tissue homeostatic maintenance through balancing self-renewal with lineage selection. Meanwhile, adult stem cells may be multipotent or unipotent, and are present in both quiescent and actively dividing states in vivo of the mammalians, which may switch to each other state in response to biophysical cues through mitochondria-mediated mechanisms, such as alterations in mitochondrial respiration and metabolism. In general, stem cells facilitate tissue repair after tissue-specific homing through various mechanisms, including immunomodulation of local microenvironment, differentiation into functional cells, cell “empowerment” via paracrine secretion, immunoregulation, and intercellular mitochondrial transfer. Interestingly, cell-source-specific features have been reported between different tissue-derived adult stem cells with distinct functional properties due to the different microenvironments in vivo, as well as differential functional properties in different tissue-derived stem cell-derived extracellular vehicles, mitochondrial metabolism, and mitochondrial transfer capacity. Here, we summarized the current understanding on roles of mitochondrial dynamics during stem cell homeostasis and aging, and lineage-specific differentiation. Also, we proposed potential unique mitochondrial molecular signature features between different source-derived stem cells and potential associations between stem cell aging and mitochondria–endoplasmic reticulum (ER) communication, as well as potential novel strategies for anti-aging intervention and healthy aging.

Mesenchymal Stem Cells (MSCs) possess unique properties that make them potential carriers for cancer therapy. MSCs have been documented to have low immunogenicity, positive safety in clinical trials, and the ability to selectively perform homing to inflammation and tumor sites. This review aims to introduce tumor tropism mechanism and effects of MSCs on tumor cells, and give an overview of MSCs in delivering gene therapeutic agents, oncolytic viruses and chemotherapeutics, as well as the application of MSCs-derived exosomes in tumor-targeted therapy.

Introduction : Mesenchymal stromal/stem cells (MSCs) hold great perspective for the therapy of a host of diseases due to regenerative and anti-inflammatory properties by differentiation into diverse cell populations, homing to damaged tissue regions, paracrine effects and release of extracellular vesicles. Areas covered : This review describes the isolation, characterization and potential use of MSCs and ADSCs for benign and malignant diseases. The MSCs may be administered as whole cells or in form of their secretome that is held responsible for most of their beneficial effects. A special constituent of the paracrine components are the extracellular vesicles (EVs) that carry a biologically potent cargo of proteins, cytokines and RNA. Expert opinion : The applications of MSCs and ADSCs are amply documented and have been investigated in preclinical models and many unregulated and a few controlled trials. Larger numbers of MSCs and ADSCs can be obtained for allogeneic transfer but imply difficulties including perseverance of the cells in vivo and possible differentiation into harmful cell types. MSC-derived cell-free preparations are easier to handle and manufacture for various applications. Especially, with the help of bioreactors, EVs can be obtained in excessive numbers and preloaded or charged with proteins, cytokines and regulatory RNA specimen to treat inflammatory diseases and cancer.

Alzheimer's disease (AD) is a chronic, progressive, and fatal neurodegenerative disorder that is characterized by memory failure, cognitive impairment, as well as behavioral and psychological manifestations. Drugs can only moderately manage, but not alleviate, clinical symptoms. Results, based on animal models, have demonstrated that cell therapy is a promising strategy for treating neurodegenerative disorders. The homing effect of mesenchymal stem cells (MSCs) replaces damaged cells, while some scholars believe that the paracrine effects play a crucial role in treating diseases. In fact, these cells have rich sources, exhibit high proliferation rates, low tumorigenicity, and immunogenicity, and have no ethical concerns. Consequently, MSCs have been used across various disease aspects, such as regulating immunity, nourishing nerves, and promoting regeneration. Deterioration of public health status have exposed both Alzheimer's patients and researchers to various difficulties during epidemics. In this review, we discuss the advances and challenges in the application of mesenchymal stem cell therapy for treatment of Alzheimer's disease.

GPR15 is a chemoattractant receptor that facilitates colon homing of regulatory and effector CD4+ T cells in health and colitis. The molecular mechanisms that control GPR15 expression are not fully known. Here we report the presence of two highly conserved aryl hydrocarbon receptor (AHR) binding sequences in a 3′ enhancer of GPR15, leading us to investigate AHR function in regulating GPR15 expression. Using luciferase reporter assays, we show that AHR activation increased GPR15 expression and requires both the AHR binding sites. Consistent with a transcriptional regulatory role, treatment with AHR agonists induce GPR15 expression on human CD4+ T cells. Using AHR-deficient mice, we demonstrate that the lack of AHR signaling drastically reduces GPR15 expression on effector/memory and Foxp3+ CD4+ T cells. In mixed bone marrow chimeras of AHR-deficient and wildtype cells, GPR15 expression was similarly diminished on AHR-deficient CD4+ effector/memory and regulatory T cells in the colon and small intestine. Furthermore, administration of AHR agonists upregulated GPR15 expression on CD4+ effector/memory T cells and increased their homing capability, especially to the colon. Collectively, our studies reveal a novel function of the AHR in regulation of GPR15 expression and increased colon trafficking of CD4+ T cells expressing GPR15.

Background One of the greatest challenges for tissue-engineered bone is the low survival rate of locally grafted cells. The cell homing technology can effectively increase the number of these grafted cells, therefore, enhancing the repair of bone defects. Here we explore the effect of fucosylation modification on the directional homing of bone marrow mesenchymal stem cells (BMSCs) and their ability to repair bone defects. Results Glycosylated BMSCs expressed high levels of the Sialyl Lewis-X (sLeX) antigen, which enabled the cells to efficiently bind to E- and P-selectins and to home to bone defect sites in vivo. Micro-CT and histological staining results confirmed that mice injected with FuT7-BMSCs showed an improved repair of bone defects compared to unmodified BMSCs. Conclusions The glycosylation modification of BMSCs has significantly enhanced their directional homing ability to bone defect sites, therefore, promoting bone repair. Our results suggest that glycosylation-modified BMSCs can be used as the source of the cells for the tissue-engineered bone and provide a new approach for the treatment of bone defects. Graphic Abstract

Hematopoietic stem/progenitor cell (HSPC) and leukemic cell homing is an important biological phenomenon that occurs through key interactions between adhesion molecules. Tethering and rolling of the cells on endothelium, the crucial initial step of the adhesion cascade, is mediated by interactions between selectins expressed on endothelium to their ligands expressed on HSPCs/leukemic cells in flow. Although multiple factors that affect the rolling behavior of the cells have been identified, molecular mechanisms that enable the essential slow and stable cell rolling remain elusive. Here, using a microfluidics-based single-molecule live cell fluorescence imaging, we reveal that unique spatiotemporal dynamics of selectin ligands on the membrane tethers and slings, which are distinct from that on the cell body, play an essential role in the rolling of the cell. Our results suggest that the spatial confinement of the selectin ligands to the tethers and slings together with the rapid scanning of a large area by the selectin ligands, increases the efficiency of selectin-ligand interactions during cell rolling, resulting in slow and stable rolling of the cell on the selectins. Our findings provide novel insights and contribute significantly to the molecular-level understanding of the initial and essential step of the homing process., Al Alwan et al. describe the tethering and rolling behaviour of leukemic cells by using a microfluidic platform that mimics the endothelial surface under flow conditions. With single-molecule live cell fluorescence imaging, they show that unique spatiotemporal dynamics of selectin ligands on the membrane tethers and slings play an essential role in the rolling of the cell.

Background The homing capacity of human mesenchymal stem cells (hMSCs) to the injured sites enables systemic administration of hMSCs in clinical practice. In reality, only a small proportion of MSCs are detected in the target tissue, which is a major bottleneck for MSC-based therapies. We still don’t know the mechanism how MSCs are chemo-attracted to certain target organ and engrafted through trans-endothelial migration. In this study, we aimed to determine the mechanism how the circulating hMSCs home to the injured liver. Methods and results When we compare the cytokine array between normal and injured mouse liver at 1-day thioacetamide (TAA)-treatment, we found that chemerin, CXCL2, and CXCL10 were higher in the injured liver than normal one. Among three, only chemerin was the chemoattractant of hMSCs in 2D- and 3D-migration assay. Analysis of the signal transduction pathways in hMSCs showed that chemerin activated the phosphorylation of JNK1/2, ERK1/2 and p38, and finally upregulated CD44, ITGA4, and MMP-2 that are involved in the transendothelial migration and extravasation of MSCs. Upstream transcription regulators of CD44, ITGA4, and MMP-2 after chemerin treatment were MZF1, GATA3, STAT3, and STAT5A. To develop chemerin as a chemoattractant tool, we cloned gene encoding the active chemerin under the CMV promoter (CMV-aChemerin). We analyzed the migration of hMSCs in the 3D model for space of the Disse, which mimics transmigration of hMSCs in the liver. CMV-aChemerin-transfected hepatocytes were more effective to attract hMSC than control hepatocytes, leading to the enhanced transendothelial migration and homing of hMSCs to liver. The homing efficiency of the intravascularly-delivered hMSCs to liver was evaluated after systemic introduction of the CMV-aChemerin plasmid packed in liposome-vitamin A conjugates which target liver. CMV-aChemerin plasmid targeting liver significantly enhanced homing efficiency of hMSCs to liver compared with control plasmid vector. Conclusions Chemerin is the newly found chemoattractant of hMSCs and may be a useful tool to manipulate the homing of the intravascularly-administered hMSC to the specific target organ.

Over the last decade, mesenchymal stem cells (MSCs) have been considered a suitable source for cell-based therapy, especially in regenerative medicine. First, the efficacy and functions of MSCs in clinical applications have been attributed to their differentiation ability, called homing and differentiation. However, it has recently been confirmed that MSCs mostly exert their therapeutic effects through soluble paracrine bioactive factors and extracellular vesicles, especially secretome. These secreted components play critical roles in modulating immune responses, improving the survival, and increasing the regeneration of damaged tissues. The secretome content of MSCs is variable under different conditions. Oxidative stress (OS) is one of these conditions that is highly important in MSC therapy and regenerative medicine. High levels of reactive oxygen species (ROS) are produced during isolation, cell culture, and transplantation lead to OS, which induces cell death and apoptosis and limits the efficacy of their regeneration capability. In turn, the preconditioning of MSCs in OS conditions contributes to the secretion of several proteins, cytokines, growth factors, and exosomes, which can improve the antioxidant potential of MSCs against OS. This potential of MSC secretome has turned it into a new promising cell-free tissue regeneration strategy.This review provides a view of MSC secretome under OS conditions, focusing on different secretome contents of MSCs and thier possible therapeutic potential against cell therapy.

Metastasis is one of the major obstacles for breast cancer patients. Limitations of current models demand the development of custom platforms to predict metastatic potential and homing choices of cancer cells. Here, two organ-on-chip (OoC) platforms, invasion/chemotaxis (IC-chip) and extravasation (EX-chip) were used for the quantitative assessment of invasion and extravasation towards specific tissues. Lung, liver and breast microenvironments were simulated in the chips using tissue specific cells embedded in matrigel. In the IC-chip, invasive MDA-MB-231, but not non-invasive MCF-7 breast cancer cells invaded into lung and liver microenvironments. In the EX-chip, MDA-MB-231 cells extravasated more into the lung compared to the liver and breast microenvironments. In addition, lung-specific MDA-MB-231 clone invaded and extravasated into the lung microenvironment more efficiently than the bone-specific clone. Both invasion/chemotaxis and extravasation results were in agreement with published clinical data. Collectively, our results show that IC-chip and EX-chip, simulating tissue specific microenvironments, can distinguish different in vivo metastatic phenotypes, in vitro. Determination of tissue specific metastatic potential of breast cancer cells is expected to improve diagnosis and help select the ideal therapy. This article is protected by copyright. All rights reserved.

Natural killer (NK) cells play an important role in innate immune responses to viral infections. Here, we review recent insights into the role of NK cells in viral infections, with particular emphasis on human studies. We first discuss NK cells in the context of acute viral infections, with flavivirus and influenza virus infections as examples. Questions related to activation of NK cells, homing to infected tissues and the role of tissue-resident NK cells in acute viral infections are also addressed. Next, we discuss NK cells in the context of chronic viral infections with hepatitis C virus and HIV-1. Also covered is the role of adaptive-like NK cell expansions as well as the appearance of CD56− NK cells in the course of chronic infection. Specific emphasis is then placed in viral infections in patients with primary immunodeficiencies affecting NK cells. Not least, studies in this area have revealed an important role for NK cells in controlling several herpesvirus infections. Finally, we address new data with respect to the activation of NK cells and NK cell function in humans infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) giving rise to coronavirus disease 2019 (COVID-19)., This Review covers the role of natural killer cells in acute and chronic viral infections, with emphasis on human infections and insights from patients with primary immunodeficiencies affecting natural killer cells. It also describes the emerging data on how natural killer cells are involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Summary Spermatogonial transplantation has been used as a standard assay for spermatogonial stem cells (SSCs). After transplantation into the seminiferous tubules, SSCs transmigrate through the blood-testis barrier (BTB) between Sertoli cells and settle in a niche. Unlike in the repair of other self-renewing systems, SSC transplantation is generally performed after complete destruction of endogenous spermatogenesis. Here, we examined the impacts of recipient conditioning on SSC homing. Germ cell ablation downregulated the expression of glial cell line-derived neurotrophic factor, which has been shown to attract SSCs to niches, implying that nonablated niches would attract SSCs more efficiently. As expected, SSCs colonized nonablated testes when transplanted into recipients with the same genetic background. Moreover, although spermatogenesis was arrested at the spermatocyte stage in Cldn11-deficient mice without a BTB, transplantation not only enhanced donor colonization but also restored normal spermatogenesis. The results show promise for the development of a new transplantation strategy to overcome male infertility., Graphical abstract, Highlights • Spermatogonial stem cells (SSCs) can engraft in nonablated testes • GFRA1+ spermatogonia are relatively resistant to busulfan • GDNF is downregulated after germ cell deficiency • SSC transplantation into Cldn11-deficient testes restores spermatogenesis, In this article, Shinohara and colleagues show that spermatogonial stem cells can colonize and produce offspring in nonablated recipients.

Summary Hematopoietic stem cells (HSCs) are typically characterized by transplantation into irradiated hosts in a highly perturbed microenvironment. Here, we show that selective and temporally controlled depletion of resident HSCs through genetic deletion of Gata2 constitutes efficient recipient conditioning for transplantation without irradiation. Strikingly, we achieved robust engraftment of donor HSCs even when delaying Gata2 deletion until 4 weeks after transplantation, allowing homing and early localization to occur in a completely non-perturbed environment. When HSCs from the congenic strains Ly5.1 and Ly5.2 were competitively transplanted, we found that the more proliferative state of Ly5.2 HSCs was associated with superior long-term engraftment when using conditioning by standard irradiation, while higher CXCR4 expression and a better homing ability of Ly5.1 HSCs strongly favored the outcome in our inducible HSC depletion model. Thus, the mode and timing of recipient conditioning challenges distinct functional features of transplanted HSCs., Graphical abstract, Highlights • Inducible gene deletion of Gata2 rapidly and selectively depletes the HSC pool • Gata2 deletion constitutes efficient recipient conditioning for HSC transplantation • The model enables detection of HSC engraftment in a non-perturbed microenvironment • Transplantation without irradiation uniquely challenges homing properties of HSCs, In this study Larsson and colleagues show that selective and temporally controlled depletion of resident hematopoietic stem cells (HSCs) through genetic deletion of Gata2 constitutes efficient recipient conditioning for transplantation without irradiation. They demonstrate that engraftment in a non-perturbed microenvironment uniquely challenges properties affecting homing and early HSC localization, that otherwise are masked in irradiated recipients.

Vascular diseases are the most prevalent cause of ischemic necrosis of tissue and organ, which even result in dysfunction and death. Vascular regeneration or artificial vascular graft, as the conventional treatment modality, has received keen attentions. However, small-diameter (diameter, Graphical abstract Image 1, Highlights • This paper reviews challenges and strategies for enhanced in situ vascularization. • Strategies for homing, adhesion and activation of EPCs and ECs are summarized. • Approaches to prevent thrombogenesis and IH for long-term lumen patency are introduced. • Immune system plays a role in modulating biological behaviors of ECs and SMCs. • Perspectives for future development of vascular grafts are proposed.

Cancer immunotherapy tools include antibodies, vaccines, cytokines, oncolytic viruses, bispecific molecules, and cellular therapies. This review will focus on adoptive cellular therapy, which involves the isolation of a patient’s own immune cells followed by their ex vivo expansion and reinfusion. The majority of adoptive cellular therapy strategies utilize T cells isolated from tumor or peripheral blood, but may utilize other immune cell subsets. T-cell therapies in the form of tumor-infiltrating lymphocytes, T-cell receptor T cells, and CAR T cells may act as “living drugs” as these infused cells expand, engraft, and persist in vivo, allowing adaptability over time and enabling durable remissions in subsets of patients. Adoptive cellular therapy has been less successful in the management of solid tumors because of poor homing, proliferation, and survival of transferred cells. Strategies are discussed, including expression of transgenes to address these hurdles. Additionally, advances in gene editing using CRISPR/Cas9 and similar technologies are described, which allow for clinically translatable gene-editing strategies to enhance the antitumor activity and to surmount the hostilities advanced by the host and the tumor. Finally, the common toxicities and approaches to mitigate these are reviewed.

The baseline composition of T cells directly impacts later response to a pathogen, but the complexity of precursor states remains poorly defined. Here we examined the baseline state of SARS-CoV-2 specific T cells in unexposed individuals. SARS-CoV-2 specific CD4+T cells were identified in pre-pandemic blood samples by class II peptide-MHC tetramer staining and enrichment. Our data revealed a substantial number of SARS-CoV-2 specific T cells that expressed memory phenotype markers, including memory cells with gut homing receptors. T cell clones generated from tetramer-labeled cells cross-reacted with bacterial peptides and responded to stool lysates in a MHC-dependent manner. Integrated phenotypic analyses revealed additional precursor diversity that included T cells with distinct polarized states and trafficking potential to other barrier tissues. Our findings illustrate a complex pre-existing memory pool poised for immunologic challenges and implicate non-infectious stimuli from commensal colonization as a factor that shapes pre-existing immunity.One Sentence SummaryPre-existing immunity to SARS-CoV-2 contains a complex pool of precursor lymphocytes that include differentiated cells with broad tissue tropism and the potential to cross-react with commensal antigens.

Infertility is a global reproductive disorder which is caused by a variety of complex diseases. Infertility affects the individual, family, and community through physical, psychological, social and economic consequences. The results from recent preclinical studies regarding stem cell-based therapies are promising. Stem cell-based therapies cast a new hope for infertility treatment as a replacement or regeneration strategy. The main features and application prospects of mesenchymal stem cells in the future of infertility should be understood by clinicians. Mesenchymal stem cells (MSCs) are multipotent stem cells with abundant source, active proliferation, and multidirectional differentiation potential. MSCs play a role through cell homing, secretion of active factors, and participation in immune regulation. Another advantage is that, compared with embryonic stem cells, there are fewer ethical factors involved in the application of MSCs. However, a number of questions remain to be answered prior to safe and effective clinical application. In this review, we summarized the recent status of MSCs in the application of the diseases related to or may cause to infertility and suggest a possible direction for future cytotherapy to infertility.