scholarly journals Capacity for stochastic self-renewal and differentiation in mammalian spermatogonial stem cells

2009 ◽  
Vol 187 (4) ◽  
pp. 513-524 ◽  
Author(s):  
Zhuoru Wu ◽  
Katherine Luby-Phelps ◽  
Abhijit Bugde ◽  
Laura A. Molyneux ◽  
Bray Denard ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Cell Types ◽  
Spermatogonial Stem Cells ◽  
Culture Conditions ◽  
Basic Question ◽  
Self Renewal ◽  
A Cell ◽  
Fate Decision ◽  
Ex Vivo Culture

Mammalian spermatogenesis is initiated and sustained by spermatogonial stem cells (SSCs) through self-renewal and differentiation. The basic question of whether SSCs have the potential to specify self-renewal and differentiation in a cell-autonomous manner has yet to be addressed. Here, we show that rat SSCs in ex vivo culture conditions consistently give rise to two distinct types of progeny: new SSCs and differentiating germ cells, even when they have been exposed to virtually identical microenvironments. Quantitative experimental measurements and mathematical modeling indicates that fate decision is stochastic, with constant probability. These results reveal an unexpected ability in a mammalian SSC to specify both self-renewal and differentiation through a self-directed mechanism, and further suggest that this mechanism operates according to stochastic principles. These findings provide an experimental basis for autonomous and stochastic fate choice as an alternative strategy for SSC fate bifurcation, which may also be relevant to other stem cell types.

Age-specific different immune responses due to capabilities of secreting primal immunoglobulins responding to unexperienced antigens

2021 ◽  
Author(s):  
JANGHO LEE ◽  
Kyoungshik Cho ◽  
Hyejin Kook ◽  
Suman Kang ◽  
Yunsung Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Immune System ◽  
Defense Mechanism ◽  
Ex Vivo ◽  
Binding Capacity ◽  
Culture Conditions ◽  
Fetal Stem Cells ◽  
Self Defense ◽  
Wide Range ◽  
Ex Vivo Culture

Abstract Among numerous studies on COVID-19, we noted that the infection and mortality rates of SARS-CoV-2 increased with age and that fetuses known to be particularly susceptible to infection were better protected despite various mutations. Hence, we established the hypothesis that a new immune system exists that forms before birth and decreases with aging. To prove this, we analyzed the components from early pregnancy fetal stem cells cultivated in various ex-vivo culture conditions simulating the environment during pregnancy. Resultingly, we confirmed that IgM, a natural antibody produced only in early B-1 cells, immunoglobulins including IgG3, which has a wide range of antigen-binding capacity and affinity, complement proteins, and antiviral proteins are induced. Our results suggest that fetal stem cells can form an independent immune system responding to unlearned antigens as a self-defense mechanism before establishing mature immune systems. Moreover, we propose the possibility of new solutions to cope with various infectious diseases based on the factors therein.

Enhanced Self-Renewal of Hematopoietic Stem Cells Mediated by the Polycomb Gene Product, Bmi-1.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1686-1686
Author(s):  
Hideyuki Oguro ◽  
Atsushi Iwama ◽  
Hiromitsu Nakauchi
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Target Genes ◽  
Ex Vivo ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Ex Vivo Culture ◽  
Deficient Mice

Abstract The Polycomb group (PcG) proteins form multiprotein complexes that play an important role in the maintenance of transcriptional repression of target genes. Loss-of-function analyses show abnormal hematopoiesis in mice deficient for PcG genes including Bmi-1, Mph-1/Rae28, M33, Mel-18, and Eed, suggesting involvement of PcG complexes in the regulation of hematopoiesis. Among them, Bmi-1 has been implicated in the maintenance of hematopoietic and leukemic stem cells. In this study, detailed RT-PCR analysis of mouse hematopoietic cells revealed that all PcG genes encoding components of the Bmi-1-containing complex, such as Bmi-1, Mph1/Rae28, M33, and Mel-18 were highly expressed in CD34−c-Kit+Sca-1+Lin− (CD34−KSL) hematopoietic stem cells (HSCs) and down-regulated during differentiation in the bone marrow. These expression profiles support the idea of positive regulation of HSC self-renewal by the Bmi-1-containing complex. To better understand the role of each component of the PcG complex in HSC and the impact of forced expression of PcG genes on HSC self-renewal, we performed retroviral transduction of Bmi1, Mph1/Rae28, or M33 in HSCs followed by ex vivo culture. After 14-day culture, Bmi-1-transduced but not Mph1/Rae28-transduced cells contained numerous high proliferative potential-colony forming cells (HPP-CFCs), and presented an 80-fold expansion of colony-forming unit-neutrophil/macrophage/Erythroblast/Megakaryocyte (CFU-nmEM) compared to freshly isolated CD34−KSL cells. This effect of Bmi-1 was comparable to that of HoxB4, a well-known HSC activator. In contrast, forced expression of M33 reduced proliferative activity and caused accelerated differentiation into macrophages, leaving no HPP-CFCs after 14 days of ex vivo culture. To determine the mechanism that leads to the drastic expansion of CFU-nmEM, we employed a paired daughter cell assay to see if overexpression of Bmi-1 promotes symmetric HSC division in vitro. Forced expression of Bmi-1 significantly promoted symmetrical cell division of daughter cells, suggesting that Bmi-1 contributes to CFU-nmEM expansion by promoting self-renewal of HSCs. Furthermore, we performed competitive repopulation assays using transduced HSCs cultured ex vivo for 10 days. After 3 months, Bmi-1-transduced HSCs manifested a 35-fold higher repopulation unit (RU) compared with GFP controls and retained full differentiation capacity along myeloid and lymphoid lineages. As expected from in vitro data, HSCs transduced with M33 did not contribute to repopulation at all. In ex vivo culture, expression of both p16INK4a and p19ARF were up-regulated. p16INK4aand p19ARF are known target genes negatively regulated by Bmi-1, and were completely repressed by transducing HSCs with Bmi-1. Therefore, we next examined the involvement of p19ARF in HSC regulation by Bmi-1 using p19ARF-deficient and Bmi-1 and p19ARF-doubly deficient mice. Although bone marrow repopulating activity of p19ARF-deficient HSCs was comparable to that of wild type HSCs, loss of p19ARF expression partially rescued the defective hematopoietic phenotypes of Bmi-1-deficient mice. In addition, transduction of Bmi-1 into p19ARF-deficient HSCs again enhanced repopulating capacity compared with p19ARF-deficient GFP control cells, indicating the existence of additional targets for Bmi-1 in HSCs. Our findings suggest that the level of Bmi-1 is a critical determinant for self-renewal of HSC and demonstrate that Bmi-1 is a novel target for therapeutic manipulation of HSCs.

Hematopoietic Stem and Progenitor Cell Fate Decisions Are Regulated By a Cell-Autonomous p190-B/TGF-β Signaling Pathway

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 467-467
Author(s):  
Ashwini S Hinge ◽  
Jyuing Xu ◽  
Eucabeth Mose ◽  
Edward F Srour ◽  
Bruce Arronow ◽  
...  
Keyword(s):  
Daughter Cell ◽  
Ex Vivo ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Daughter Cells ◽  
Lineage Differentiation ◽  
A Cell ◽  
Fate Decision ◽  
Serial Transplantation ◽  
Inhibitor Treatment

Hematopoietic stem cells (HSC) are undifferentiated cells that self-renew and produce all mature blood and immune cells in order to sustain life-long hematopoiesis. The molecular mechanisms that determine HSC fate decisions still remain poorly understood. Identifying these factors is of great biological and clinical importance, as alteration in HSC fate decisions will eventually lead to HSC depletion or malignant HSC expansion. We previously showed that p190-B GTPase Activating Protein (GAP), a negative regulator of Rho activity, is a critical regulator of HSC self-renewal. P190-B loss enhanced long-term engraftment during serial transplantation; but, surprisingly, without altering their survival, blood lineage differentiation and the balance between quiescence and proliferation (Xu et al, Blood). Therefore, we hypothesize that p190-B regulates HSC self-renewal by controlling a HSC fate decision to self-renew or to differentiate, so-called asymmetric versus symmetric self-renewal divisions. To test this, we compared patterns of single WT and p190-B-/- HSC (i.e. Lin-c-kit+Sca-1+CD150+CD48- [LSK-SLAM]) divisions over serial transplantation. First, we confirmed that the division rate of single LSK-SLAM was similar between the genotypes. Then, we performed the pair daughter cell assay to examine the ability of LSK-SLAM to generate daughter cells that retain multipotent lineage differentiation potential. We found that non-transplanted (CTL) HSC gave rise to 93% symmetric self-renewal divisions (i.e. both daughter cells are multipotent, neutrophil, erythroid, macrophage and megakaryocyte (nemM)), and 7% were asymmetric (only one daughter cell is multipotent). Interestingly, after 2 rounds of transplantation (2T), WT HSCs produced only 50% symmetric self-renewal divisions whereas p190-B-deficient HSCs maintained 92% symmetric self-renewal divisions. Hence, p190-B modulates asymmetric/symmetric self-renewal divisions to control HSC regeneration over serial transplantation. Using transcriptional profiling and chemical screening, we identified, quite unexpectedly, the transforming growth factor beta (TGFβ) pathway as a regulatory pathway mediating p190-B functions. Expression of TGFβ responsive genes (mRNA expression of tgif2, smurf2) were higher in 2T-WT than in 2T-p190-B–/–-HSCs and CTL HSC. To assess if increased TGFβ signaling affected HSC self-renewing decisions, we used the TGF-β inhibitor, SB431542, ex vivo. TGFβ inhibitor treatment of 2T-WT LSK-SLAM in pair daughter cell assay converted their fate decision to produce 90% symmetric self-renewal divisions; TGFβ inhibitor treatment ex vivo for 48h of WT LT-HSCs isolated from primary transplanted mice enhanced engraftment into secondary mice. Importantly, TGFβ inhibitor-treatment of mice over serial transplantation reversed transplant-related WT HSC decline as it enhanced HSC pool regeneration in BM and long-term HSC engraftment. Interestingly, it did not alter HSC cell cycle parameters or the relative heterogeneity of the HSC pool or blood lineage maturation. Mechanistically, p190-B appeared to regulate TGF-β signaling in a cell-autonomous manner by controlling bioactive TGF-β protein within HSCs. Finally we observed that TGFβ mediated its effect via non-canonical p38MAPK signaling. This study identifies a previously unknown p190-B/TGFβ signaling network that governs HSC fate decisions to self-renew or to differentiate, without altering HSC quiescence or development of the progeny. This also reveals an unexpected role for TGFβ as a regulator of HSC fate beyond its well-defined role in HSC hibernation. The clinical implications are important for the field of HSC expansion and bone marrow transplantation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals BCR-ABL-transformed GMP as myeloid leukemic stem cells

2008 ◽  
Vol 105 (46) ◽  
pp. 17967-17972 ◽  
Author(s):  
Yosuke Minami ◽  
Scott A. Stuart ◽  
Tomokatsu Ikawa ◽  
Yong Jiang ◽  
Asoka Banno ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mouse Model ◽  
Knockout Mouse ◽  
Ex Vivo ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Leukemic Stem Cells ◽  
Self Renewal ◽  
Established Line ◽  
Ex Vivo Culture

During blast crisis of chronic myelogenous leukemia (CML), abnormal granulocyte macrophage progenitors (GMP) with nuclear β-catenin acquire self-renewal potential and may function as leukemic stem cells (Jamieson et al. N Engl J Med, 2004). To develop a mouse model for CML-initiating GMP, we expressed p210BCR-ABL in an established line of E2A-knockout mouse BM cells that retain pluripotency in ex vivo culture. Expression of BCR-ABL in these cells reproducibly stimulated myeloid expansion in culture and generated leukemia-initiating cells specifically in the GMP compartment. The leukemogenic GMP displayed higher levels of β-catenin activity than either the nontransformed GMP or the transformed nonGMP, both in culture and in transplanted mouse BM. Although E2A-deficiency may have contributed to the formation of leukemogenic GMP, restoration of E2A-function did not reverse BCR-ABL-induced transformation. These results provide further evidence that BCR-ABL-transformed GMP with abnormal β-catenin activity can function as leukemic stem cells.

scholarly journals Wound healing in the liver with particular reference to stem cells

1998 ◽  
Vol 353 (1370) ◽  
pp. 877-894 ◽  
Author(s):  
Malcolm Alison ◽  
Matthew Golding ◽  
El–Nasir Lalani ◽  
Catherine Sarraf
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Biliary Tree ◽  
Target Population ◽  
Cell Types ◽  
Oval Cells ◽  
Inborn Errors ◽  
Ductal Cells ◽  
Biological Interest ◽  
A Cell

The efficiency of liver regeneration in response to the loss of hepatocytes is widely acknowledged, and this is usually accomplished by the triggering of normally proliferatively quiescent hepatocytes into the cell cycle. However, when regeneration is defective, tortuous ductular structures, initially continuous with the biliary tree, proliferate and migrate into the surrounding hepatocyte parenchyma. In humans, these biliary cells have variously been referred to as ductular structures, neoductules and neocholangioles, and have been observed in many forms of chronic liver disease, including cancer. In experimental animals, similar ductal cells are usually called oval cells, and their association with impaired regeneration has led to the conclusion that they are the progeny of facultative stem cells. Oval cells are of considerable biological interest as they may represent a target population for hepatic carcinogens, and they may also be useful vehicles for ex vivo gene therapy for the correction of inborn errors of metabolism. This review proposes that the liver harbours stem cells that are located in the biliary epithelium, that oval cells are the progeny of these stem cells, and that these cells can undergo massive expansion in their numbers before differentiating into hepatocytes. This is a conditional process that only occurs when the regenerative capacity of hepatocytes is overwhelmed, and thus, unlike the intestinal epithelium, the liver is not behaving as a classical, continually renewing, stem cell–fed lineage. We focus on the biliary network, not merely as a conduit for bile, but also as a cell compartment with the ability to proliferate under appropriate conditions and give rise to fully differentiated hepatocytes and other cell types.

scholarly journals Bioinformatics Analysis of Transcriptomic Data Reveals Refined Functional Networks for the Self-Renewal of Mouse Spermatogonial Stem Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Min Wang ◽  
Wene Zhao ◽  
Fuqiang Wang ◽  
Xiufeng Ling ◽  
Daozhen Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Signaling Pathways ◽  
Bioinformatics Analysis ◽  
Cell Types ◽  
Spermatogonial Stem Cells ◽  
Expression Index ◽  
Extrinsic Factors ◽  
Self Renewal ◽  
Proliferation And Differentiation ◽  
Disease Associations

Spermatogonial stem cells (SSCs) are exquisitely regulated to reach a balance between proliferation and differentiation in the niche of seminiferous epithelium. Several extrinsic factors such as GDNF are reported to switch the transition, activating various intrinsic signaling pathways. Transcriptomics analysis could provide a comprehensive landscape of gene expression and regulation. Here, we reanalyzed a previously published transcriptome of two cell types (standing for self-renewing and differentiating SSCs correspondingly). First, we proposed a new parameter, the expression index, to sort the genes considering both absolute and relative expression levels. Using a dynamic statistical model, we identified a list of 1119 candidate genes for SSC self-renewal with the best enrichment of canonical markers. Finally, based on interaction relations, we further optimized the list and constructed a refined network containing integrated information of interactions, expression alternations, biological functions, and disease associations. Further annotation of the 521 refined genes involved in the network revealed an enrichment of well-studied signaling pathways. We believe that the refined network could help us better understand the regulation of SSCs’ fates, as well as find novel regulators or targets for SSC self-renewal or preservation of male fertility.

scholarly journals Maintaining the male germline: regulation of spermatogonial stem cells

2010 ◽  
Vol 205 (2) ◽  
pp. 133-145 ◽  
Author(s):  
Kyle Caires ◽  
Johnathan Broady ◽  
Derek McLean
Keyword(s):  
Stem Cells ◽  
Male Fertility ◽  
Adult Stem Cells ◽  
Spermatogonial Stem Cells ◽  
Seminiferous Tubules ◽  
Cellular Mechanisms ◽  
Self Renewal ◽  
Research Findings ◽  
A Cell ◽  
Transplantation Assay

Spermatogonial stem cells (SSCs) are a self-renewing population of adult stem cells capable of producing progeny cells for sperm production throughout the life of the male. Regulation of the SSC population includes establishment and maintenance of a niche microenvironment in the seminiferous tubules of the testis. Signaling from somatic cells within the niche determines the fate of SSCs by either supporting self-renewal or initiating differentiation leading to meiotic entry and production of spermatozoa. Despite the importance of these processes, little is known about the biochemical and cellular mechanisms that govern SSC fate and identity. This review discusses research findings regarding systemic, endocrine, and local cues that stimulate somatic niche cells to produce factors that contribute to the homeostasis of SSCs in mammals. In addition to their importance for male fertility, SSCs represent a model for the investigation of adult stem cells because they can be maintained in culture, and the presence, proliferation, or loss of SSCs in a cell population can be determined with the use of a transplantation assay. Defining the mechanisms that regulate the self-renewal and differentiation of SSCs will fundamentally improve the understanding of male fertility and provide information about the regulation of adult stem cells in other tissues.

scholarly journals Sphingolipid Perturbation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 170-170
Author(s):  
Stephanie Zhi-Juan Xie ◽  
Laura Garcia Prat ◽  
Veronique Voisin ◽  
Alex Murison ◽  
Olga I. Gan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Ex Vivo ◽  
Fold Increase ◽  
Chromatin Accessibility ◽  
Self Renewal ◽  
Cellular Activation ◽  
Hematopoietic Stem ◽  
Risk Of Malignancy ◽  
Ex Vivo Culture

Abstract The hematopoietic stem cells (HSC) field has long been perplexed by how the blood system d (~10e12 cells produced daily) - yet hematologic malignancies remain relatively rare. The risk of malignancy is mitigated in part by a complex hierarchy in which the quiescent long-term hematopoietic stem cells (LT-HSC) with high self-renewal capacity undergo a restricted number of cell divisions. Nonetheless, such a high production demand over a lifetime raises an inherent risk of malignancy due to DNA replication errors, misfolded proteins and metabolic stress that cause cellular damage in HSC. Previously, HSC dormancy, largely thought to be controlled by transcription factor networks, was held responsible for preventing mutation acquisition. However, recent studies suggest that LT-HSC contain critical cellular networks centered around the coordination of distinct HSC metabolic programs with proteostasis, which serve as crucial decision nodes to balance persistence or culling of HSC for lifelong blood production. While HSC culling mechanisms are known, the linkage between cellular stress programs and the self-renewal properties that underlie human HSC persistence remains unknown. Here, we ask how this HSC fate choice is influenced by lipid biosynthesis - an underexplored area of HSC metabolism. We observed a distinct sphingolipid transcriptional signature in human HSC and examined the consequences of sphingolipid perturbation in human cord blood (CB) stem cells during ex vivo activation. DEGS1 (Delta 4-Desaturase, Sphingolipid 1) is the final enzyme in de novo sphingolipid synthesis, converting dihydroceramide (dhCer) to ceramide (Cer); ablation of DEGS1 either genetically or by treatment with the synthetic retinoid fenretinide/N-(4-hydroxyphenyl) retinamide (4HPR) is sufficient to activate autophagy in mouse cells and human cell lines. DEGS1 gene expression was higher in HSC than in progenitors and was significantly increased in LT-HSC following 6 hours of cytokine stimulation, suggesting that it plays a role in cellular activation. Sphingolipid composition was altered in CB cultured with 4HPR for 8 days with an increase in dhCer levels and decrease in Cer levels shown by lipidomics. Remarkably, 4HPR treatment significantly increased in vitro colony forming efficiency from LT-HSC (50% over control), but not from short-term HSC or granulocyte-macrophage progenitors. Ex vivo 4HPR treatment of CB followed by serial xenotransplantation resulted in a 2.5-fold increase in long-term repopulation cell (LTRC) frequency over control-treated cells, suggesting that 4HPR treatment affects HSC self-renewal. RNA-seq analysis showed that 4HPR activates a set of proteostatic quality control (QC) programs that coalesce around the unfolded protein response (UPR) and autophagy, the latter confirmed by immunofluorescence and flow cytometry in CB stem cells. Ex vivo culture perturbs these programs and results in loss of chromatin accessibility at sites associated with uncultured LT-HSC as determined by ATAC-Seq. Addition of 4HPR to the culture activates these proteostatic programs to sustain immunophenotypic and functional HSC. These results suggest that ceramide, the central component to all sphingolipids, may act as a "lipid biostat" for measuring cellular stress and activating stress responses. We further asked if 4HPR could synergize with known compounds to enhance HSC self-renewal. Treatment of CB with a combination of 4HPR plus CD34+ agonists UM171 and StemRegenin-1 during ex vivo culture maintains a chromatin state more similar to uncultured LT-HSC as demonstrated by ATAC-seq, and led to a 4-fold increase in serial repopulating ability in xenotransplant assays over treatment with UM171 and SR1 alone. These results suggest that sphingolipid perturbation not only activates proteostatic mechanisms that protect HSC organelles from damage incurred during cellular activation, but also regulates the landscape of chromatin accessibility in cultured HSC when combined with CD34+ agonists. This work identifies a new linkage between sphingolipid metabolism, proteostatic QC systems and HSC self-renewal, and identifies novel strategies by which to expand HSC numbers and improve HSC quality for clinical applications. Disclosures Takayama: Megakaryon co. Ltd.: Research Funding.

scholarly journals SMALL Molecules Mediated Hematopoietic STEM and Progenitor CELLS Expansion for GENE Editing Application

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5803-5803
Author(s):  
Abisha Crystal C ◽  
Saravanabhavan Thangavel ◽  
Shaji Ramachandran Velayudhan ◽  
Alok Srivastava ◽  
Aneesha Nath ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Migration ◽  
Hematopoietic Stem Cells ◽  
Small Molecules ◽  
Gene Editing ◽  
Ex Vivo ◽  
Culture Conditions ◽  
Hematopoietic Stem ◽  
Colony Forming Cell ◽  
Ex Vivo Culture

Abstract Genome editing of Hematopoietic stem Cells has revolutionized the treatment strategies for genetic disorders. Despite this, it still remains a great challenge as hematopoietic stem cells tend to lose its stem-ness during the ex vivo culture and gene editing process. The need for large dose of CD34+ HSPCs for manipulation makes it a seemingly difficult strategy. Recent works suggest that the potential effects of small molecules in expanding cord blood HSPCs ex vivo promoting self-renewal and delaying differentiation. We screened several reported small molecules to identify a condition that promotes the expansion of adult HSPCs for gene manipulation process. The mobilized Peripheral blood HSPCs are purified and cultured with a cytokine cocktail. Along with the cytokine cocktail, we tested several small molecules and in different combinations. Expression of cell surface receptors were analysed by FACS after 12 days of ex vivo culture. Our screening identified a unique culture condition that expanded the primitive stem cell population (CD34+/CD133+/CD90+cells) along with the early progenitors (CD34+/CD133+) and the progenitors (CD34+). Our culture conditions expanded the primitive cells by 20 folds compared to the mock treated cells. Our treatment release experiments suggested that the expansion is due to our culture conditions and are reversible.The colony forming cell (CFC) assay showed about 30 fold increase in the numbers of multilineage colony forming cell (CFU-GEMM) thereby ensuring the proliferation and differentiation capacity of expanded HSPCs. Their differentiation ability was also confirmed by ex vivo differentiation into Megakaryocytes. Our treatment conditions reduced the apoptosis rate during the ex vivo culture and improved their cell migration response towards SDF. The reduced reactive oxygen species levels and increased CXCR4 expression were observed in our expanded HSPCs and these might be the possible reasons for the low apoptosis and better cell migration respectively. Disclosures No relevant conflicts of interest to declare.

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