The Hematopoietic Stem Cells Could Be Switched From Leukemic Cell Lines

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4845-4845
Author(s):  
Jianda Hu ◽  
Ting Yang ◽  
Liangfang Zhu ◽  
Xiaofeng Luo ◽  
Xiaohong Yuan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Surface ◽  
Hematopoietic Stem Cells ◽  
Conflicts Of Interest ◽  
Embryonic Stem ◽  
Restriction Enzyme Digestion ◽  
Hematopoietic Stem ◽  
Primary Mouse ◽  
Hes Cells

Abstract Background The hematopoietic potential from induced pluripotent stem cells (iPS) has been explored for some years. However, the direct reprogramming from the blood cells to hematopoietic progenitors bypass the pluripotency is even more attractive for the clinical practice. Methods The lentiviral vector encoding human reprogramming factors (Oct-4, Sox2, c-Myc, Klf4FOSCK) were transfected along with packaging plasmid pCMV-dR8.91 and envelope plasmid pCMV-VSV-G in 293T package cells to produce lentiviral particles. The construction was then confirmed by RT-PCR and restriction enzyme digestion anaysis, and the lentivirus titer was determined using GFP/DAPI based on cell count by Image J software. Primary mouse embryo fibroblast (PMEF) feeder cells were isolated and prepared from CF-1 inbred mouse strain to help maintain pluripotency and to provide a cellular matrix for stem cells growing. Lastly, the lentivirus carrying OSCK factors was used totransduce HL-60 cells in three consecutive rounds of spin-infection on the prepared feeder layers with an interval of 12 hours, while the lentivirus carrying GFP served as a negative control. The cell clusters were picked based on morphology and alkaline phosphatase(AP) staining. The stem cell properties were tested by the expression of cell surface antigens using Flow cytometry. and the mRNA expression of OCT4, SOX2, C-MYC,KLF4,etc. by QT-PCR. Results The lentiviral particles were successful packaged and used to infect HL-60 cells. We occasionally observed some Human embryonic stem cells (hES) cell-like colonies in between the cells around 14 days after infection. These cell colonies also showed similarity to hES cells in feeder dependency. Detection of cell surface CD34 by FCM showed that HL-60 cells were switched to be a hematopoietic fate, expression of CD34 from 1.77% to 98.42%. Simultaneously, expressions of the myeloid antigen CD13, CD117 decreased. The gene expressions of OCT4, SOX2 indicated that the exogenous gene were down-regulation or silence while the endogenous gene were up-regulation. However, the cell colonies can survive only for a short time which might due to the absence of the survival factors they require or the first hematopoietic microenvironment, like the yolk sac. Conclusion After being reprogrammed, the HL-60 cell derived colonies showed the similarity to hES cells in morphology, feeder dependency and the expression of stem cell antigens. However, they may need an appropriate microenvironment at different time points to be programmed into primitive hematopoietic stem cells. Disclosures: No relevant conflicts of interest to declare.

The Ethics of Embrionic Stem Cells Research

2019 ◽  
pp. 244-263
Author(s):  
Alexandra Huidu
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Embryonic Stem Cell ◽  
Stem Cell Research ◽  
Embryonic Stem ◽  
Modern Medicine ◽  
Embryonic Stem Cell Research ◽  
Hematopoietic Stem ◽  
Research Fields

Embrionic stem cells research, as opposed to hematopoietic stem cells research, has always stirred up many controversies of ethical nature that have projected their effects in the specialized doctrine of the domain of medical bioethics and law. Some of these controversies have been transposed at the legislative level (both by international normative acts and by the national laws of the states) while others are not yet de object of consensus. All that is not transposed by law remains in the exclusive sphere of ethics, so the ethical discussion in embryonic stem cell research is not only relevant for today's modern medicine but also of the utmost importance for a category of specialists in various research fields.

Characterization of Histone Modifications on Lineage-Affiliated Genes During Hematopoietic Stem Cell Differentiation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4784-4784
Author(s):  
Chen Fangping ◽  
Huarong Tang
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Histone Modifications ◽  
Conflicts Of Interest ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Low Level ◽  
Lineage Specific Genes

Abstract Abstract 4784 Hematopoietic stem cells (HSCs) are multipotent stem cells capable of self-renewal and multi-lineage differentiation. Though it has been shown that multiple factors take part in the maintenance of HSCs’ multipotency and differentiation potential, the mechanisms are unclear. Recent studies showed that histone modifications play an important role in maintenance of embryonic stem cells pluripotency and differentiation. To characterize the histone modification patterns of different lineages, HSCs were collected from umbilical cord blood and induced to differentiate to granulocytic, erythroid, and megakarytic in vitro. genes during HSC differentiation. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) technology was adopted to investigate the dynamic changes of histone modifications on lineage specific transcription factors and lineage–affiliated genes. Our results showed a certain level of H4 acetylation and H3 acetylation together with high level of H3K4me2 and low level of H3K4me3, H3K9me3 and H3K27me3 were present in lineage specific genes in CD34+CD38- HSCs. As CD34+CD38- cells differentiated, the modification level of acH3, acH4, H3K4me2, H3K9me3 and H3K27me3 on lineage specific genes remained the same, while H3K4me3 level increased greatly. In non-lineage specific genes, the acH3 and acH4 levels decreased, and H3K4me3 level remain at low level, while H3K9me3 and H3K27me3 levels increased. Thus, our data suggested that histone modifications played an important role in maintenaning the multipotency and differentiation capability of hematopoietic stem cells. Disclosures: No relevant conflicts of interest to declare.

Bcr-Abl Impairs T Cell Development From Murine Induced Pluripotent Stem Cells and Hematopoietic Stem Cells; A Partial Explanation for the Concept That Ph+ Clone Never Involves T Cell Lineage in CML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3748-3748
Author(s):  
Bidisha Chanda ◽  
Kiyoko Izawa ◽  
Ratanakanit Harnprasopwat ◽  
Keisuke Takahashi ◽  
Seiichiro Kobayashi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Pluripotent Stem Cells ◽  
Conflicts Of Interest ◽  
T Cell Development ◽  
Cell Lineage ◽  
Cell Development ◽  
Hematopoietic Stem

Abstract Abstract 3748 Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder generally believed to originate from a hematopoietic stem cell carrying the BCR-ABL fusion gene, which generally encodes 210kD and 190kD constitutively active tyrosine kinases termed as p210 and p190, respectively. In spite of the putative stem cell origin and the competence for differentiation toward mature B cells, there is a longstanding consensus that CML never involves the T cell lineage at least in chronic phase. To gain insight into this apparent conflict, we used in vitro T cell differentiation model from murine pluripotent stem cells (PSCs) as well as hematopoietic stem cells (HSCs). C57BL/6 MEFs were reprogrammed using a polycistronic lentiviral Tet-On vector encoding human Oct4, Sox2 and Klf4, which were tandemly linked via porcine teschovirus-1 2A peptides, together with another lentiviral vector expressing rtTA driven by the EF-1a promoter. Almost all the vector sequences including the transgenes were deleted by adenovirus-mediated transduction of Crerecombinase after derivation of iPSCs, and only remnant 291-bp LTRs containing a single loxP site remained in the genome. A clone of MEF-iPSCs were retrovirally transduced with p190DccER, a ligand-controllable p190-estrogen receptor fusion protein, whose tyrosine kinase activity absolutely depends on 4-hydroxytamoxyfen (4-HT).For T cell lineage differentiation, p190DccER-MEF-iPSCs were recovered from a feeder-free culture supplemented with LIF and plated onto a subconfluent OP9-DL1 monolayer in the presence of Flt3 ligand and IL7 with or without 0.5 mM 4-HT.After 3 weeks of culture, iPSC-derived blood cells were collected and subjected to FACS analysis for their lineage confirmation. About 70% of lymphocyte-like cells from the 4-HT(-) culture expressed CD3, but only 20% of counterparts from the 4-HT(+)culture expressed CD3, suggesting impaired T cell development by Bcr-Abl. Next, c-Kit+Sca1+Lin− (KSL) bone marrow cells were prepared by FACS from 8-weeks old C57BL/6 mice treated with 5-FU. KSL cells were similarly transduced with p190DccER and were subjected to the OP9-DL1co-culture system with or without 0.5 mM 4-HT.After 2 weeks of culture, 90% of lymphocytes from the 4-HT(-)culture revealed CD3+TCRβ+ phenotype, but only 30% of those were double positive in the presence of 4-HT(+). In addition, 96% of lymphocytes from the 4-HT(-) culture progressed to the DN2 stage with c-Kit−CD44+CD25+phenotype, whereas 40% of those from the 4-HT(+) culture arrested at the DN1 stage showing c-Kit+CD44+CD25−.Since IL7 plays a central role at the stage from DN1 to DN2 of progenitor T cells, Bcr-Abl is suggested to impair T cell development possibly through interfering with the IL7 signal. The precise mechanism underlying impaired T lymphopoiesis by Bcr-Abl is under investigation. Disclosures: No relevant conflicts of interest to declare.

Metabolic Regulation of Hematopoietic Stem Cells During Stress

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-42-SCI-42
Author(s):  
Toshio Suda
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Metabolic Regulation ◽  
Conflicts Of Interest ◽  
Hypoxia Inducible Factor ◽  
Ros Generation ◽  
Hematopoietic Stem

Abstract Abstract SCI-42 Tissue homeostasis over the life of an organism relies on both self-renewal and multipotent differentiation of stem cells. Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Adult HSCs are kept quiescent during the cell cycle in the endosteal niche of the bone marrow. Normal HSCs maintain intracellular hypoxia, stabilize the hypoxia-inducible factor-1a (HIF-1a) protein, and generate ATP by anaerobic metabolism. In HIF-1a deficiency, HSCs became metabolically aerobic, lost cell cycle quiescence, and finally became exhausted. An increased dose of HIF-1a protein in VHL-mutated HSCs and their progenitors induced cell cycle quiescence and accumulation of HSCs in the bone marrow (BM), which were not transplantable. This metabolic balance promotes HSC maintenance by limiting the production of reactive oxygen species (ROS), but leaves HSCs susceptible to changes in redox status (1). We have performed the metabolomic analysis in HSCs. Upregulation of pyruvate dehydrogenase kinases enhanced the glycolytic pathway, cell cycle quiescence, and stem cell capacity. Thus, HSCs directly utilize the hypoxic microenvironment to maintain their slow cell cycle by HIF-1a-dependent metabolism. Downregulation of mitochondrial metabolism might be reasonable, since it reduces ROS generation. On the other hand, at the time of BM transplantation, HSCs activate oxidative phosphorylation to acquire more ATP for proliferation. Autophagy also energizes HSCs by providing amino acids during transplantation. ATG (autophagy-related) 7 is essential for transplantation and metabolic homeostasis. The relationship between mitochondrial heat shock protein, mortalin, and metabolism in HSCs will also be discussed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Putative “Stemness” Gene Jam-B Is Not Required for Maintenance of Stem Cell State in Embryonic, Neural, or Hematopoietic Stem Cells

2006 ◽  
Vol 26 (17) ◽  
pp. 6557-6570 ◽  
Author(s):  
Takehisa Sakaguchi ◽  
Masazumi Nishimoto ◽  
Satoru Miyagi ◽  
Atsushi Iwama ◽  
Yohei Morita ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Expression Profiles ◽  
Embryonic Stem ◽  
Mutant Mice ◽  
Mouse Development ◽  
Specific Expression ◽  
Hematopoietic Stem ◽  
Undifferentiated Escs

ABSTRACT Many genes have been identified that are specifically expressed in multiple types of stem cells in their undifferentiated state. It is generally assumed that at least some of these putative “stemness” genes are involved in maintaining properties that are common to all stem cells. We compared gene expression profiles between undifferentiated and differentiated embryonic stem cells (ESCs) using DNA microarrays. We identified several genes with much greater signal in undifferentiated ESCs than in their differentiated derivatives, among them the putative stemness gene encoding junctional adhesion molecule B (Jam-B gene). However, in spite of the specific expression in undifferentiated ESCs, Jam-B mutant ESCs had normal morphology and pluripotency. Furthermore, Jam-B homozygous mutant mice are fertile and have no overt developmental defects. Moreover, we found that neural and hematopoietic stem cells recovered from Jam-B mutant mice are not impaired in their ability to self-renew and differentiate. These results demonstrate that Jam-B is dispensable for normal mouse development and stem cell identity in embryonic, neural, and hematopoietic stem cells.

Growth Factor Independence 1 b (Gfi1b) as a New Regulator of Hematopoietic Stem Cell Fate

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 837-837
Author(s):  
Cyrus Khandanpour ◽  
Lothar Vassen ◽  
Marie-Claude Gaudreau ◽  
Christian Kosan ◽  
Tarik Moroy
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Fate ◽  
Conflicts Of Interest ◽  
Fold Increase ◽  
Surface Proteins ◽  
Expression Array ◽  
Hematopoietic Stem

Abstract Abstract 837 Donor matched transplantation of bone marrow or hematopoietic stem cells (HSCs) are widely used to treat hematological malignancies, but are associated with high mortality. Methods for expansion of HSC numbers and their mobilization into the bloodstream of a donor could significantly improve therapy. We show here that the zinc finger transcriptional repressor Gfi1b is highly expressed in hematopoietic stem cells (defined as CD 150+, CD 48-, Lin-, Sca1+ and c-kit+) cells and is down-regulated more than 10 fold upon differentiation into multipotential progenitors (defined as CD 150+ or CD150-, CD 48+, Lin-, Sca1+ and c-kit+). Constitutive germline deletion of Gfi1b is lethal at midgestation due to impaired development of erythrocytes and megakaryocytes. We have therefore developed a conditional knock-out of Gfi1b to study its role specifically in the adult hematopoietic system. Deletion of Gfi1b leads to a 30-fold increase of HSC numbers in bone marrow and around a100 fold increase in spleen and peripheral blood. This was due to a higher rate of HSCs undergoing cell cycling. Concomitantly, the number of quiescent HSCs was reduced 5–6 times. We then performed an gene expression array of wt and Gfi1b deficient HSCs and observed that loss of Gfi1b leads to an altered RNA expression of integrins and adhesion molecules, for instance CXCR4, VCAM-1 and Tenascin C, which usually retain HSCs in a dormant state in the endosteal niche. These changes were also confirmed on protein level. Finally, we could observe a higher levels of Reactive Oxygen Species (ROS) in the Gfi1b deficient HSCs compared to wt HSCs. We verified whether elevated level of ROS are causative for the expansion of HSCs and noticed that application of N-Acetyl-Cystein, which counteracts the effects of ROS, limits significantly the expansion of HSCs, underscoring the important role of ROS in the expansion of Gfi1b deficient HSCs. Despite markedly increased proliferation, Gfi1b-/- HSCs can reconstitute lymphoid and myeloid lineages to the same extent as wt HSCs when transplanted in competition with wt HSCs. Furthermore, Gfi1b deficient HSCs also feature an expansion after transplantation and expand 5–10 fold more than wt HSC when transplanted initially in equal numbers with wt HSCs. It is possible that lower expression of CXCR4, VCAM-1 and other surface proteins leads to release and egression of Gfi1b deficient HSCs from the hypoxic endosteal stem cell niche and exposes the HSCs to more oxygen which in turn increases ROS levels. Elevated ROS could promote entry of Gfi1b-/- HSCs into cell cycle. In conclusion Gfi1b regulates HSC dormancy, pool size and potentially also the egress and mobilization of HSCs and might offer a new therapeutic approach to improve human HSC transplantation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Embryonic stem cell-derived hematopoietic stem cells

2005 ◽  
Vol 102 (52) ◽  
pp. 19081-19086 ◽  
Author(s):  
Y. Wang ◽  
F. Yates ◽  
O. Naveiras ◽  
P. Ernst ◽  
G. Q. Daley
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Embryonic Stem Cell ◽  
Embryonic Stem ◽  
Hematopoietic Stem

scholarly journals Mir-99 Regulates Normal and Leukemic Stem Cell Function

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1469-1469
Author(s):  
Mona Khalaj ◽  
Carolien Woolthuis ◽  
Wenhuo Hu ◽  
Benjamin Heath Durham ◽  
Christopher Y. Park
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Peripheral Blood ◽  
Cell Function ◽  
Conflicts Of Interest ◽  
Ectopic Expression ◽  
Gene Set Enrichment Analysis ◽  
Hematopoietic Stem

Abstract Acute myeloid leukemia (AML) is composed of functionally heterogeneous cells including leukemic stem cells (LSCs), which exhibit the ability to self-renew and propagate disease. It is thought that failure of common chemotherapy regimens is due to insufficient eradication of LSCs. However, the mechanisms that maintain stem cell function in the hematopoietic system are not well understood. MicroRNAs play an important role in the regulation of normal and malignant hematopoietic stem cells. Our studies showed that miR-99, a miRNA highly expressed in AML patient cell populations enriched for LSC activity, is among the most highly expressed miRNAs in hematopoietic stem cells (HSCs), suggesting that miR-99 plays a role in regulating normal HSCs as well as LSCs. To test the role of miR-99 in normal hematopoiesis, we knocked down (KD) miR-99 in mouse HSCs (Lin-cKit+Sca1+CD34-SLAM+), which resulted in ~3 fold reduced methylcellulose colony formation upon secondary plating (P=0.01), as well as accelerated granulopoiesis as demonstrated by increased Gr1+Mac1+ cells 7 days after culture initiation (P<0.01), suggesting that miR-99 functions to suppresses differentiation. Consistent with this model, transplantation assays demonstrated >10-fold reduction in long-term engraftment capacity of miR-99 KD compared to scrambled controls (P=0.0004). In addition, Ki-67/DAPI staining of stably engrafted miR-99 KD hematopoietic stem and progenitor cells (HSPCs) showed increased cell cycling, demonstrating that miR-99 also maintains HSPC quiescence. Gene set enrichment analysis (GSEA) of RNA-sequencing data generated from stably engrafted Lin-Sca-1+c-Kit+ cells revealed that miR-99 KD induces significant depletion of LT-HSC gene signatures (P<0.001) and induction of a late progenitor signature (P<0.001), providing further evidence that miR-99 normally functions to maintain HSPCs in the undifferentiated state. To test whether miR-99 maintains LSCs, we performed miR-99 KD experiments using the MLL-AF9 retroviral mouse model. miR-99 KD resulted in a significant extension in survival in secondary transplants compared to scrambled controls (median 92 days vs. 48 days, P<0.001). Evaluation of the bone marrow at the time of death revealed ~2.5 fold decrease in the frequency of LSCs (P<0.01) and ~2 fold increase in the percentage of cycling LSCs (in SG2M) (P<0.001). Analysis of RNA-seq data from miR-99 KD LSCs revealed induction of a differentiated normal progenitor signature (P<0.001) and depletion of a shared HSC/LSC gene signature (P=0.05). Giemsa staining of peripheral blood showed miR-99 KD also induced a significant increase in the number of differentiated myeloid precursors in the peripheral blood (P<0.001), reminiscent of AML differentiation-inducing agents used in the clinic such as ATRA. Consistent with a role in regulating leukemic blast differentiation, microRNA-Seq data from the 153 AML patients in the TCGA database revealed that miR-99 expression inversely correlated with their French-American-British classifications, with low expression levels associated with M4 and M5 subtypes. Compatible with a role in maintaining LSCs, miR-99 KD in a primary AML sample reduced long-term engraftment upon xenotransplantation into NSG mice, and the engrafting cells displayed increased CD14 expression. Together, these data demonstrate that similar to normal HSPCs, miR-99 maintains LSCs function. As miR-99 functions to maintain both LSCs and HSCs, we asked which miR-99 target genes mediate miR-99 KD phenotypes. To address this question, we performed a shRNA library-based forward genetic screen designed to rescue the reduced HSC function following miR-99 KD. We designed 180 shRNAs against 45 predicted miR-99 targets that we identified as upregulated upon acute miR-99 KD in mouse HSPCs. Among the conserved miR-99 targets, Hoxa1, a member of the Hox family of transcription factors, was among the top hits, with all 4 shRNAs being enriched compared to controls. Ectopic expression of Hoxa1 in MonoMac6 AML cells was sufficient to induce differentiation, a phenotype similar to miR-99 KD. These data indicate that Hoxa1 is an important downstream mediator of miR-99 function. Disclosures No relevant conflicts of interest to declare.

TIMP-1 Deficiency Subverts Cell Cycle Dynamics In HSCs.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1545-1545
Author(s):  
Lara Rossi ◽  
Margaret A. Goodell
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Conflicts Of Interest ◽  
Biological Role ◽  
Biological Behavior ◽  
Hematopoietic Stem ◽  
Cell Cycle Inhibitors ◽  
Cell Cycle Dynamics

Abstract Abstract 1545 Although TIMP-1 was initially described as a mere inhibitor of Metalloproteinases (MMPs), recent findings have offered a different perspective on its biological role, contributing to unveil its multifaceted nature. In addition to inhibiting MMP activity, TIMP-1 has been proven to play MMP-independent, cytokine-like activities and to be involved in the regulation of numerous biological functions, including cell proliferation and survival. We therefore hypothesized that TIMP-1 might be involved in the homeostatic regulation of hematopoietic stem cells (HSCs), whose biological behavior is the synthesis of both microenvironmental and intrinsic cues. Bone marrow hematopoietic stem cells (HSCs) were isolated from TIMP-1-/- mice based on the phenotype Side Population c-Kit+Lin- Sca-1+ (SPKLS). In vitro cultural assays as well as in vivo transplantation assays were employed to investigate how TIMP-1 obliteration affects murine hematopoiesis. Cell-cycle dynamics in KO SPKLS HSCs were characterized by Pyronin Y/Hoechst staining, Ki-67 staining, as well as evaluation of RNA expression of cell cycle inhibitors, such as p53, p57, and p21. We found that TIMP-1-/- mice have decreased HSC numbers and, consistent with this finding, TIMP-1-/- HSCs display reduced capability of long-term repopulation. Interestingly, the cell cycle distribution of TIMP-1-/- LT-HSCs is profoundly distorted, with a consistent proportion of the stem cell pool arrested in the G1 phase, suggesting that TIMP-1 is intrinsically involved in the regulation of the HSC proliferation dynamics. Of note, TIMP-1-/- HSCs present decreased levels of CD44 glycoprotein, whose expression has been proven to be controlled by p53, the master regulator of the G1/S transition. Interestingly, p53 RNA levels are indeed increased in TIMP-1-/- SPKLS HSCs compared to controls. Likewise, the expression level of other cell-cycle inhibitors, such as p57 and p21, were found to be higher in KO SPKLS HSCs, indicating a disregulation of cell-cycle dynamics.Our study highlights a novel biological role of TIMP-1 in the regulation of the HSC compartment and suggest a novel mechanism presiding over stem cell quiescence in the framework of the BM milieu. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document