• Skeletal aging
• bone marrow
• cellular senescence
• stem cells

• Bioactive peptides
• Hematopoiesis
• Integrins
• Intracellular calcium
• Mesenchymal stromal cells
• Protein kinase C
• Signaling modifiers

• Humans
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism
• Signal Transduction/drug effects
• Regenerative Medicine/methods
• Bone Marrow Cells/cytology
• Bone Marrow Cells/drug effects
• Bone Marrow Cells/metabolism
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/drug effects
• Hematopoietic Stem Cells/metabolism
• Cell Proliferation/drug effects
• Hematopoiesis/drug effects
• Cells, Cultured

• cell therapy
• hematopoietic stem cell transplantation
• immune recovery

• Humans
• Hematopoietic Stem Cell Transplantation/methods
• Cell- and Tissue-Based Therapy/methods
• Animals
• Graft vs Host Disease/immunology
• Graft vs Host Disease/prevention & control
• Graft vs Host Disease/therapy

• ML-1 dated October 26, 2023. The Government of the Novosibirsk oblast

• Anti-inflammatory response
• Bone marrow-mesenchymal stromal cells (BM-MSCs)
• Hematopoietic support
• MSC reprogramming
• Transcriptomic analysis

• Humans
• Mesenchymal Stem Cells/metabolism
• Early Growth Response Protein 1/genetics
• Early Growth Response Protein 1/metabolism
• Transcriptome
• Gene Expression Profiling
• Cells, Cultured
• Hematopoietic Stem Cells/metabolism
• Bone Marrow Cells/metabolism

• cell homing
• clinical use
• drug delivery
• mesenchymal stem cell
• nanoparticles

• Humans
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/immunology
• Animals
• Drug Delivery Systems
• Neoplasms/therapy
• Neoplasms/immunology

• children
• graft failure
• graft vs. host disease
• hematopoietic stem cell transplantation
• hemorrhagic cystitis
• mesenchymal stromal cells
• poor graft function

• cancer microenvironment
• cell biology

• Humans
• Endothelial Cells
• Neoplasms
• Stromal Cells
• Carcinogenesis
• Hematologic Neoplasms
• Tumor Microenvironment

• Jilin University Bethune Program (No. 2023B16). the "Medicine + X" cross-innovation team of Bethune Medical Department of Jilin University "Leading the Charge with Open Competition" construction project (No. 2022JBGS04).

Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency. Despite its increased use, the mortality rate for patients undergoing this procedure remains high, mainly due to the perceived risk of exacerbating graft-versus-host disease (GVHD). However, even with immunosuppressive agents, some patients still develop GVHD. Advanced mesenchymal stem/stromal cell (MSC) strategies have been proposed to achieve better therapeutic outcomes, given their immunosuppressive potential. However, the efficacy and trial designs have varied among the studies, and some research findings appear contradictory due to the challenges in characterizing the in vivo effects of MSCs. This review aims to provide real insights into this clinical entity, emphasizing diagnostic, and therapeutic considerations and generating pathophysiology hypotheses to identify research avenues. The indications and timing for the clinical application of MSCs are still subject to debate.

• Mesenchymal stem/stromal cells
• Graft-versus-host disease
• Immunomodulatory
• Adaptive immunity
• Exosomes

• aplastic anemia
• bone marrow failure
• cell therapy
• mesenchymal stem cells

• DNA-damage response
• genome editing
• hematopoietic stem and progenitor cells
• hematopoietic support
• mesenchymal stromal cells

• Humans
• Animals
• Mice
• Gene Editing
• CRISPR-Cas Systems
• Hematopoietic Stem Cells
• Mesenchymal Stem Cells
• Hematopoietic Stem Cell Transplantation/methods

Bone marrow transplantation (BMT) can be applied to both hematopoietic and nonhematopoietic diseases; nonetheless, it still comes with a number of challenges and limitations that contribute to treatment failure. Bearing this in mind, a possible way to increase the success rate of BMT would be cotransplantation of mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) to improve the bone marrow niche and secrete molecules that enhance the hematopoietic engraftment.

To analyze HSC and MSC characteristics and their interactions through cotransplantation in murine models.

We searched for original articles indexed in PubMed and Scopus during the last decade that used HSC and MSC cotransplantation and in vivo BMT in animal models while evaluating cell engraftment. We excluded in vitro studies or studies that involved graft versus host disease or other hematological diseases and publications in languages other than English. In PubMed, we initially identified 555 articles and after selection, only 12 were chosen. In Scopus, 2010 were identified, and six were left after the screening and eligibility process.

Of the 2565 articles found in the databases, only 18 original studies met the eligibility criteria. HSC distribution by source showed similar ratios, with human umbilical cord blood or animal bone marrow being administered mainly with a dose of 1 × 10⁷ cells by intravenous or intrabone routes. However, MSCs had a high prevalence of human donors with a variety of sources (umbilical cord blood, bone marrow, tonsil, adipose tissue or fetal lung), using a lower dose, mainly 10⁶ cells and ranging 10⁴ to 1.5 × 10⁷ cells, utilizing the same routes. MSCs were characterized prior to administration in almost every experiment. The recipient used was mostly immunodeficient mice submitted to low-dose irradiation or chemotherapy. The main technique of engraftment for HSC and MSC cotransplantation evaluation was chimerism, followed by hematopoietic reconstitution and survival analysis. Besides the engraftment, homing and cellularity were also evaluated in some studies.

The preclinical findings validate the potential of MSCs to enable HSC engraftment in vivo in both xenogeneic and allogeneic hematopoietic cell transplantation animal models, in the absence of toxicity.

• Mesenchymal stem cells
• Hematopoietic stem cells
• Bone marrow transplantation
• Co-transplantation
• Hematopoietic reconstitution
• Engraftment

Bone marrow mesenchymal stromal cells (MSCs) play a crucial role in the regulation of hematopoiesis. These cells affect the process through direct cell–cell contact, as well as releasing various trophic factors and extracellular vehicles (EVs) into the bone marrow microenvironment. MSC-derived EVs (MSC-EVs) are prominent intercellular communication tolls enriched with broad-spectrum bioactive factors such as proteins, cytokines, lipids, miRNAs, and siRNAs. They mimic some effects of MSCs by direct fusion with hematopoietic stem cells (HSC) membranes in the bone marrow (BM), thereby affecting HSC fate. MSC-EVs are attractive scope in cell-free therapy because of their unique capacity to repair BM tissue and regulate proliferation and differentiation of HSCs. These vesicles modulate the immune system responses and inhibit graft-versus-host disease following hematopoietic stem cell transplantation (HSCT). Recent studies have demonstrated that MSC-EVs play an influential role in the BM niches because of their unprecedented capacity to regulate HSC fate. Therefore, the existing paper intends to speculate upon the preconditioned MSC-EVs as a novel approach in HSCT.

• Extracellular vesicles
• Hematopoietic stem cell transplantation
• Hematopoietic stem cells
• Mesenchymal stem cells

Gene therapy involves a substantial loss of hematopoietic stem and progenitor cells (HSPC) during processing and homing. Intra-BM (i.b.m.) transplantation can reduce homing losses, but prior studies have not yielded promising results. We studied the mechanisms involved in homing and engraftment of i.b.m. transplanted and i.v. transplanted genetically modified (GM) human HSPC. We found that i.b.m. HSPC transplantation improved engraftment of hematopoietic progenitor cells (HPC) but not of long-term repopulating hematopoietic stem cells (HSC). Mechanistically, HPC expressed higher functional levels of CXCR4 than HSC, conferring them a retention and homing advantage when transplanted i.b.m. Removing HPC and transplanting an HSC-enriched population i.b.m. significantly increased long-term engraftment over i.v. transplantation. Transient upregulation of CXCR4 on GM HSC-enriched cells, using a noncytotoxic portion of viral protein R (VPR) fused to CXCR4 delivered as a protein in lentiviral particles, resulted in higher homing and long-term engraftment of GM HSC transplanted either i.v. or i.b.m. compared with standard i.v. transplants. Overall, we show a mechanism for why i.b.m. transplants do not significantly improve long-term engraftment over i.v. transplants. I.b.m. transplantation becomes relevant when an HSC-enriched population is delivered. Alternatively, CXCR4 expression on HSC, when transiently increased using a protein delivery method, improves homing and engraftment specifically of GM HSC.

• Genetic Therapy
• Hematopoietic Stem Cell Transplantation
• Hematopoietic Stem Cells/metabolism
• Humans
• Receptors, CXCR4/genetics
• Receptors, CXCR4/metabolism
• Signal Transduction

• R01 DK102890 NIDDK NIH HHS

Haematopoietic stem cells (HSCs) reside in the bone marrow and are supported by the specialised microenvironment, a niche to maintain HSC quiescence. To deal with haematopoietic equilibrium disrupted during inflammation, HSCs are activated from quiescence directly and indirectly to generate more mature immune cells, especially the myeloid lineage cells. In the process of proliferation and differentiation, HSCs gradually lose their self-renewal potential. The extensive inflammation might cause HSC exhaustion/senescence and malignant transformation. Here, we summarise the current understanding of how HSC functions are maintained, damaged, or exhausted during acute, prolonged, and pathological inflammatory conditions. We also highlight the inflammation-altered HSC niche and its impact on escalating the insults on HSCs.

• bone marrow niche
• haematopoietic stem cells
• inflammation

• Anticancer strategy
• Immunomodulation
• MSC
• Signaling pathway
• Therapeutic mechanism
• Tumor-homing

• Animals
• Humans
• Immunomodulation
• Mesenchymal Stem Cell Transplantation/methods
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/immunology
• Neoplasms/immunology
• Neoplasms/therapy
• Translational Science, Biomedical

• National Natural Science Foundation Regional Innovation and Development
• National Major Scientific and Technological Special Project for “Significant New Drugs Development”
• Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China
• Development Program of China
• National Natural Science Foundation of China
• Sichuan Science and Technology Program

• engraftment
• graft vs host disease
• hematopoietic stem cell transplantation
• outcomes
• relapse
• survival

Overall, the human organism requires the production of ∼1 trillion new blood cells per day. Such goal is achieved via hematopoiesis occurring within the bone marrow (BM) under the tight regulation of hematopoietic stem and progenitor cell (HSPC) homeostasis made by the BM microenvironment. The BM niche is defined by the close interactions of HSPCs and non-hematopoietic cells of different origin, which control the maintenance of HSPCs and orchestrate hematopoiesis in response to the body’s requirements. The activity of the BM niche is regulated by specific signaling pathways in physiological conditions and in case of stress, including the one induced by the HSPC transplantation (HSCT) procedures. HSCT is the curative option for several hematological and non-hematological diseases, despite being associated with early and late complications, mainly due to a low level of HSPC engraftment, impaired hematopoietic recovery, immune-mediated graft rejection, and graft-versus-host disease (GvHD) in case of allogenic transplant. Mesenchymal stromal cells (MSCs) are key elements of the BM niche, regulating HSPC homeostasis by direct contact and secreting several paracrine factors. In this review, we will explore the several mechanisms through which MSCs impact on the supportive activity of the BM niche and regulate HSPC homeostasis. We will further discuss how the growing understanding of such mechanisms have impacted, under a clinical point of view, on the transplantation field. In more recent years, these results have instructed the design of clinical trials to ameliorate the outcome of HSCT, especially in the allogenic setting, and when low doses of HSPCs were available for transplantation.

• bone marrow niche
• hematopoietic (stem) cell transplantation
• hematopoietic stem and progenitor cell
• immunoregulation
• mesenchymal stromal cells

• bone biomechanics
• demineralized bone
• radiation therapy

• cell biology
• stem cells

• Engraftment
• Infections
• Mesenchymal stromal cells
• Mucositis

• bone marrow
• chimerism
• hematopoietic stem cell
• immune tolerance
• mesenchymal stem cells
• regulatory T cells
• solid organ transplant
• vascular composite allograft

• Animals
• Biological Specimen Banks
• Bone Marrow Cells/immunology
• Bone Marrow Transplantation/adverse effects
• Donor Selection
• Graft Rejection/immunology
• Graft Rejection/prevention & control
• Graft Survival
• Hematopoietic Stem Cell Transplantation/adverse effects
• Hematopoietic Stem Cells/immunology
• Histocompatibility
• Humans
• Immunosuppressive Agents/therapeutic use
• Mesenchymal Stem Cell Transplantation/adverse effects
• Mesenchymal Stem Cells/immunology
• Phenotype
• Tissue Donors
• Transplantation Chimera/immunology
• Transplantation Tolerance
• Treatment Outcome

• R43 AI155196 NIAID NIH HHS

Since the late 1980s, mice have been repopulated with human hematopoietic cells to study the fundamental biology of human hematopoiesis and immunity, as well as a broad range of human diseases in vivo. Multiple mouse recipient strains have been developed and protocols optimized to efficiently generate these “humanized” mice. Here, we review three guiding principles that have been applied to the development of the currently available models: (1) establishing tolerance of the mouse host for the human graft; (2) opening hematopoietic niches so that they can be occupied by human cells; and (3) providing necessary support for human hematopoiesis. We then discuss four remaining challenges: (1) human hematopoietic lineages that poorly develop in mice; (2) limited antigen-specific adaptive immunity; (3) absent tolerance of the human immune system for its mouse host; and (4) sub-functional interactions between human immune effectors and target mouse tissues. While major advances are still needed, the current models can already be used to answer specific, clinically-relevant questions and hopefully inform the development of new, life-saving therapies.

• cancer
• hematopoiesis
• humanized mice
• immunity
• immunotherapies
• infectious diseases

• BM phantoms
• biomimetic 3-D scaffolds
• bone and marrow
• bone marrow organoids
• drug resistance
• hematological cancer
• tissue engineering

• R01 CA154491 NCI NIH HHS
• R01CA154491 NIH HHS

• CD34+ HSCs
• EPO
• TGFβ1
• conditioned medium
• mesenchymal stromal cells

• Adipose-derived stromal cells
• Hematopoiesis
• Mesenchymal stromal cells
• Stem cells
• Therapy

Cotransplantation of mesenchymal stem cells (MSCs) with hematopoietic stem cells (HSCs) has been widely reported to promote HSC engraftment and enhance marrow stromal regeneration. The present study aimed to define whether MSC conditioned medium could recapitulate the effects of MSC cotransplantation. Mouse bone marrow (BM) was partially ablated by the administration of a busulfan and cyclophosphamide (Bu–Cy)-conditioning regimen in BALB/c recipient mice. BM cells (BMCs) isolated from C57BL/6 mice were transplanted via tail vein with or without tonsil-derived MSC conditioned medium (T-MSC CM). Histological analysis of femurs showed increased BM cellularity when T-MSC CM or recombinant human pleiotrophin (rhPTN), a cytokine readily secreted from T-MSCs with a function in hematopoiesis, was injected with BMCs. Microstructural impairment in mesenteric and BM arteriole endothelial cells (ECs) were observed after treatment with Bu–Cy-conditioning regimen; however, T-MSC CM or rhPTN treatment restored the defects. These effects by T-MSC CM were disrupted in the presence of an anti-PTN antibody, indicating that PTN is a key mediator of EC restoration and enhanced BM engraftment. In conclusion, T-MSC CM administration enhances BM engraftment, in part by restoring vasculature via PTN production. These findings highlight the potential therapeutic relevance of T-MSC CM for increasing HSC transplantation efficacy.

• bone marrow engraftment
• bone marrow transplantation
• mesenchymal stem cell conditioned medium
• pleiotrophin
• tonsil mesenchymal stem cells
• vascular endothelium

• Animals
• Bone Marrow Transplantation
• Carrier Proteins/pharmacology
• Cell Survival/drug effects
• Culture Media, Conditioned/pharmacology
• Cytokines/pharmacology
• Endothelium/drug effects
• Female
• Human Umbilical Vein Endothelial Cells/cytology
• Human Umbilical Vein Endothelial Cells/drug effects
• Humans
• Male
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/drug effects
• Mesenteric Arteries/drug effects
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Palatine Tonsil/cytology

• HI18C2392 Korea Health Industry Development Institute

The bone marrow (BM) niche regulates multiple hematopoietic stem cell (HSC) processes. Clinical treatment for hematological malignancies by HSC transplantation often requires preconditioning via total body irradiation, which severely and irreversibly impairs the BM niche and HSC regeneration. Novel strategies are needed to enhance HSC regeneration in irradiated BM. We compared the effects of EGF, FGF2, and PDGFB on HSC regeneration using human mesenchymal stem cells (MSCs) that were transduced with these factors via lentiviral vectors. Among the above niche factors tested, MSCs transduced with PDGFB (PDGFB-MSCs) most significantly improved human HSC engraftment in immunodeficient mice. PDGFB-MSC-treated BM enhanced transplanted human HSC self-renewal in secondary transplantations more efficiently than GFP-transduced MSCs (GFP-MSCs). Gene set enrichment analysis showed increased antiapoptotic signaling in PDGFB-MSCs compared with GFP-MSCs. PDGFB-MSCs exhibited enhanced survival and expansion after transplantation, resulting in an enlarged humanized niche cell pool that provide a better humanized microenvironment to facilitate superior engraftment and proliferation of human hematopoietic cells. Our studies demonstrate the efficacy of PDGFB-MSCs in supporting human HSC engraftment.

• GvHD
• HSCs
• MSCs
• engraftment
• extracellular vesicles
• primed

• Acute myeloid leukemia
• Cancer therapy
• Cell cycle arrest
• Hematologic malignancy
• Mesenchymal stem cells

• Tabriz University of Medical Sciences

Mesenchymal stromal cells (MSC) may exert their functions by the release of extracellular vesicles (EV). Our aim was to analyze changes induced in CD34⁺ cells after the incorporation of MSC‐EV. MSC‐EV were characterized by flow cytometry (FC), Western blot, electron microscopy, and nanoparticle tracking analysis. EV incorporation into CD34⁺ cells was confirmed by FC and confocal microscopy, and then reverse transcription polymerase chain reaction and arrays were performed in modified CD34⁺ cells. Apoptosis and cell cycle were also evaluated by FC, phosphorylation of signal activator of transcription 5 (STAT5) by WES Simple, and clonal growth by clonogenic assays. Human engraftment was analyzed 4 weeks after CD34⁺ cell transplantation in nonobese diabetic/severe combined immunodeficient mice. Our results showed that MSC‐EV incorporation induced a downregulation of proapoptotic genes, an overexpression of genes involved in colony formation, and an activation of the Janus kinase (JAK)‐STAT pathway in CD34⁺ cells. A significant decrease in apoptosis and an increased CD44 expression were confirmed by FC, and increased levels of phospho‐STAT5 were confirmed by WES Simple in CD34⁺ cells with MSC‐EV. In addition, these cells displayed a higher colony‐forming unit granulocyte/macrophage clonogenic potential. Finally, the in vivo bone marrow lodging ability of human CD34⁺ cells with MSC‐EV was significantly increased in the injected femurs. In summary, the incorporation of MSC‐EV induces genomic and functional changes in CD34⁺ cells, increasing their clonogenic capacity and their bone marrow lodging ability. stem cells2019;37:1357–1368

• Engraftment
• Extracellular vesicles
• Hematopoietic stem cells
• Mesenchymal stromal cells
• Stem cell transplantation

• AKT signaling
• CD34
• M2-10B4
• bone marrow stromal cells (BMSCs)
• cobblestone-area-forming-cells (CAFC) assay
• cocultures
• conditioned medium (CM)
• hematopoietic stem cells (HSCs)
• long-term culture-initiating cell (LTC-IC) assay
• mesenchymal stem/stromal cells (MSCs)

• Expansion of hematopoietic stem cells
• Hematopoiesis
• Hematopoietic progenitors
• Hematopoietic stem cell markers
• Hematopoietic stem cells
• In vitro assays
• In vivo assays
• Primordial germ cells
• Stem cell purification
• Very small embryonic-like stem cells

• Cell Proliferation
• Cell Separation
• Fetal Blood/cytology
• Hematopoietic Stem Cell Transplantation
• Hematopoietic Stem Cells/cytology
• Humans

Mesenchymal stromal cells (MSCs) are key elements in the bone marrow (BM) niche where they interact with hematopoietic stem progenitor cells (HSPCs) by offering physical support and secreting soluble factors, which control HSPC maintenance and fate. Although necessary for their maintenance, MSCs are a rare population in the BM, they are plastic adherent and can be ex vivo expanded to reach numbers adequate for clinical use. In light of HSPC supportive properties, MSCs have been employed in phase I/II clinical trials of hematopoietic stem cell transplantation (HSCT) to facilitate engraftment of hematopoietic stem cells (HSCs). Moreover, they have been utilized to expand ex vivo HSCs before clinical use. The available clinical evidence from these trials indicate that MSC administration is safe, as no acute and long-term adverse events have been registered in treated patients, and may be efficacious in promoting hematopoietic engraftment after HSCT. In this review, we critically discuss the role of MSCs as component of the BM niche, as recent advances in defining different mesenchymal populations in the BM have considerably increased our understanding of this complex environment. Moreover, we will revise published literature on the use of MSCs to support HSC engraftment and expansion, as well as consider potential new MSC application in the clinical context of ex vivo gene therapy with autologous HSC.

• apoptosis
• immunosuppression
• mesenchymal stem cells
• severe aplastic anemia

• Gene targeting
• Hemophilia A
• Hepatocytes
• Human embryonic stem cells
• Mesenchymal stem cells
• Ribosomal DNA

Hematopoietic stem cells (HSCs) are multipotent stem cells, with self-renewal ability as well as ability to generate all blood cells. Mesenchymal stem cells (MSCs) are multipotent stem cells, with self-renewal ability, and capable of differentiating into a variety of cell types. MSCs have supporting effects on hematopoiesis; through direct intercellular communications as well as secreting cytokines, chemokines, and extracellular vesicles (EVs). Recent investigations demonstrated that some biological functions and effects of MSCs are mediated by their EVs. MSC-EVs are the cell membrane and endosomal membrane compartments, which are important mediators in the intercellular communications. MSC-EVs contain some of the molecules such as proteins, mRNA, siRNA, and miRNA from their parental cells. MSC-EVs are able to inhibit tumor, repair damaged tissue, and modulate immune system responses. MSC-EVs compared to their parental cells, may have the specific safety advantages such as the lower potential to trigger immune system responses and limited side effects. Recently some studies demonstrated the effect of MSC-EVs on the expansion, differentiation, and clinical applications of HSCs such as improvement of hematopoietic stem cell transplantation (HSCT) and inhibition of graft versus host disease (GVHD). HSCT may be the only therapeutic choice for patients who suffer from malignant and non-malignant hematological disorders. However, there are several severe side effects such GVHD that restricts the successfulness of HSCT. In this review, we will discuss the most important effects of MSCs and MSC-EVs on the improvement of HSCT, inhibition and treatment of GVHD, as well as, on the expansion of HSCs.

• Expansion
• Graft versus host disease
• Hematopoietic stem cells
• Mesenchymal stem cell-derived extracellular vesicl
• Transplantation

Acquired aplastic anemia (AA) is a type of bone marrow failure (BMF) syndrome characterized by partial or total bone marrow (BM) destruction resulting in peripheral blood (PB) pancytopenia, which is the reduction in the number of red blood cells (RBC) and white blood cells (WBC), as well as platelets (PLT). The first-line treatment option of AA is given by hematopoietic stem cell (HSCs) transplant and/or immunosuppressive (IS) drug administration. Some patients did not respond to the treatment and remain pancytopenic following IS drugs. The studies are in progress to test the efficacy of adoptive cellular therapies as mesenchymal stem cells (MSCs), which confer low immunogenicity and are reliable allogeneic transplants in refractory severe aplastic anemia (SAA) cases. Moreover, bone marrow stromal cells (BMSC) constitute an essential component of the hematopoietic niche, responsible for stimulating and enhancing the proliferation of HSCs by secreting regulatory molecules and cytokines, providing stimulus to natural BM microenvironment for hematopoiesis. This review summarizes scientific evidences of the hematopoiesis improvements after MSC transplant, observed in acquired AA/BMF animal models as well as in patients with acquired AA. Additionally, we discuss the direct and indirect contribution of MSCs to the pathogenesis of acquired AA.

The inflamed bone marrow niche shortly after total body irradiation (TBI) is known to contribute to loss of hematopoietic stem cells in terms of their number and function. In this study, autologous bone marrow transfer (AL-BMT) was evaluated as a strategy for mitigating hematopoietic form of the acute radiation syndrome by timing the collection phase (2 h after irradiation) and reinfusion (24 h after irradiation) using mice as a model system. Collection of bone marrow (BM) cells (0.5 × 10⁶ total marrow cells) 2 h after lethal TBI rescued different subclasses of hematopoietic stem and progenitor cells (HSPCs) from the detrimental inflammatory and damaging milieu in vivo. Cryopreservation of collected graft and its reinfusion 24 h after TBI significantly rescued mice from lethal effects of irradiation (65% survival against 0% in TBI group on day 30th) and hematopoietic depression. Transient hypometabolic state (HMS) induced 2 h after TBI effectively preserved the functional status of HSPCs and improved hematopoietic recovery even when BM was collected 8 h after TBI. Homing studies suggested that AL-BMT yielded similar percentages for different subsets of HSPCs when compared to syngeneic bone marrow transfer. The results suggest that the timing of collection, and reinfusion of graft is crucial for the success of AL-BMT.

• autologous bone marrow transfer
• hematopoietic stem cells
• hematopoietic syndrome
• homing
• ionizing radiation
• mitigation

Bone marrow microenvironment is fundamental for hematopoietic homeostasis. Numerous efforts have been made to reproduce or manipulate its activity to facilitate engraftment after hematopoietic stem cell transplantation but clinical results remain unconvincing. This probably reflects the complexity of the hematopoietic niche. Recent data have demonstrated the fundamental role of stromal and myeloid cells in regulating hematopoietic stem cell self-renewal and mobilization in the bone marrow. In this study we unveil a novel interaction by which bone marrow mesenchymal stromal cells induce the rapid differentiation of CD11b⁺ myeloid cells from bone marrow progenitors. Such an activity requires the expression of nitric oxide synthase-2. Importantly, the administration of these mesenchymal stromal cell-educated CD11b⁺ cells accelerates hematopoietic reconstitution in bone marrow transplant recipients. We conclude that the liaison between mesenchymal stromal cells and myeloid cells is fundamental in hematopoietic homeostasis and suggests that it can be harnessed in clinical transplantation.

• Blood cells
• Clinical trials
• Hematopoietic differentiation
• Induced pluripotent stem cells
• Patent landscape

• Animals
• Cell Differentiation/physiology
• Cell- and Tissue-Based Therapy/methods
• Hematopoietic Stem Cells/cytology
• Humans
• Induced Pluripotent Stem Cells/cytology

Mesenchymal stromal cells (MSCs) are currently being investigated for use in a wide variety of clinical applications. For most of these applications, systemic delivery of the cells is preferred. However, this requires the homing and migration of MSCs to a target tissue. Although MSC homing has been described, this process does not appear to be highly efficacious because only a few cells reach the target tissue and remain there after systemic administration. This has been ascribed to low expression levels of homing molecules, the loss of expression of such molecules during expansion, and the heterogeneity of MSCs in cultures and MSC culture protocols. To overcome these limitations, different methods to improve the homing capacity of MSCs have been examined. Here, we review the current understanding of MSC homing, with a particular focus on homing to bone marrow. In addition, we summarize the strategies that have been developed to improve this process. A better understanding of MSC biology, MSC migration and homing mechanisms will allow us to prepare MSCs with optimal homing capacities. The efficacy of therapeutic applications is dependent on efficient delivery of the cells and can, therefore, only benefit from better insights into the homing mechanisms.

• Mesenchymal stromal cells
• Homing
• Bone marrow
• Homing receptors
• Extravasation