Role of Hematopoietic Stem and Progenitor Cells in the Origination of Mature B-cell Lymphomas

2016 ◽  
pp. 93-111
Keyword(s):  
B Cell ◽  
Progenitor Cells ◽  
B Cell Lymphomas ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Role of HMGA2 in human hematopoietic stem and progenitor cells

2013 ◽  
Vol 41 (8) ◽  
pp. S44
Author(s):  
Praveen Kumar ◽  
Aurélie Baudet ◽  
Ineke De Jong ◽  
Jonas Larsson
Keyword(s):  
Progenitor Cells ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Investigating The Role Of ARAP3 In The Regulation Of Hematopoietic Stem and Progenitor Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2409-2409
Author(s):  
Yiwen Song ◽  
Sonja Vermeren ◽  
Wei Tong
Keyword(s):  
Endothelial Cells ◽  
Plasma Membrane ◽  
Progenitor Cells ◽  
Hematopoietic Cells ◽  
Conditional Knockout ◽  
Ph Domain ◽  
Hematopoietic Stem ◽  
Normal Peripheral Blood ◽  
Stem And Progenitor Cells

Abstract ARAP3 is a member of the dual Arf-and-Rho GTPase-activating proteins (GAP) family, functioning specifically to inactivate its substrates Arf6 and RhoA GTPases. ARAP3 is translocated to the plasma membrane after PIP3 binding to the first two of its five PH domains, facilitating its GAP activity in a PI3K-mediated manner. Rho family GTPases are found to play critical roles in many aspects of hematopoietic stem and progenitor cells (HSPCs), such as engraftment and migration, while a role for Arf family GTPases in hematopoiesis is less defined. Previous studies found that either exogenous ARAP3 expression in epithelial cells or RNAi-mediated ARAP3 depletion in endothelial cells disrupts F-actin or lamellipodia formation, respectively, resulting in a cell rounding phenotype and failure to spread. This implies that ARAP3 control of Arf6 and RhoA is tightly regulated, and maintaining precise regulation of ARAP3 levels is crucial to actin organization in the cell. Although ARAP3 was first identified in porcine leukocytes, its function in the hematopoietic system is incompletely understood. Germline deletion of Arap3 results in embryonic lethality due to angiogenic defects. Since endothelial cells are important for the emergence of HSCs during embryonic development, early lethality precludes further studying the role of ARAP3 in definitive hematopoiesis. Therefore, we generated several transgenic mouse models to manipulate ARAP3 in the hematopoietic compartment: (1) Arap3fl/fl;Vav-Cretg conditional knockout mice (CKO) deletes ARAP3 specifically in hematopoietic cells, (2) Arap3fl/fl;VE-Cadherin -Cretg CKO mice selectively deletes ARAP3 in embryonic endothelial cells and thereby hematopoietic cells, and (3) Arap3R302,3A/R302,3A germline knock-in mice (KI/KI) mutates the first PH domain to ablate PI3K-mediated ARAP3 activity in all tissues. We found an almost 100% and 90% excision efficiency in the Vav-Cretg- and VEC-Cretg- mediated deletion of ARAP3 in the bone marrow (BM), respectively. However, the CKO mice appear normal in steady-state hematopoiesis, showing normal peripheral blood (PB) counts and normal distributions of all lineages in the BM. Interestingly, we observed an expansion of the Lin-Scal+cKit+ (LSK) stem and progenitor compartment in the CKO mice. This is due to an increase in the multi-potent progenitor (MPP) fraction, but not the long-term or short-term HSC (LT- or ST-HSC) fractions. Although loss of ARAP3 does not alter the frequency of phenotypically-characterized HSCs, we performed competitive BM transplantation (BMT) studies to investigate the functional impact of ARAP3 deficiency. 500 LSK cells from Arap3 CKO (Arap3fl/fl;Vav-Cretg and Arap3fl/fl;VEC-Cretg) or Arap3fl/fl control littermate donors were transplanted with competitor BM cells into irradiated recipients. We observed similar donor-derived reconstitution and lineage repopulation in the mice transplanted with Arap3fl/fl and Arap3 CKO HSCs. Moreover, Arap3 CKO HSCs show normal reconstitution in secondary transplants. Arap3 KI/KI mice are also grossly normal and exhibit an expanded MPP compartment. Importantly, Arap3KI/KI LSKs show impaired reconstitution compared to controls in the competitive BMT assays. Upon secondary and tertiary transplantation, reconstitution in both PB and BM diminished in the Arap3KI/KI groups, in contrast to sustained reconstitution in the control group. Additionally, we observed a marked skewing towards the myeloid lineage in Arap3KI/KI transplanted secondary and tertiary recipients. These data suggest a defect in HSC function in Arap3KI/KI mice. Myeloid-skewed reconstitution also points to the possibility of selection for “myeloid-primed” HSCs and against “balanced” HSCs, as HSCs exhaust during aging or upon serial transplantation. Taken together, our data suggest that ARAP3 plays a non-cell-autonomous role in HSCs by regulating HSC niche cells. Alternatively, the ARAP3 PH domain mutant that is incapable of locating to the plasma membrane in response to PI3K may exert a novel dominant negative function in HSCs. We are investigating mechanistically how ARAP3 controls HSC engraftment and self-renewal to elucidate the potential cell-autonomous and non-cell-autonomous roles of ARAP3 in HSCs. In summary, our studies identify a previously unappreciated role of ARAP3 as a regulator of hematopoiesis and hematopoietic stem and progenitor cell function. Disclosures: No relevant conflicts of interest to declare.

scholarly journals p53-dependent induction of P2X7 on hematopoietic stem and progenitor cells regulates hematopoietic response to genotoxic stress

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Lin Tze Tung ◽  
HanChen Wang ◽  
Jad I. Belle ◽  
Jessica C. Petrov ◽  
David Langlais ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Whole Body ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Stem And Progenitor Cells ◽  
Hematopoietic Response

AbstractStem and progenitor cells are the main mediators of tissue renewal and repair, both under homeostatic conditions and in response to physiological stress and injury. Hematopoietic system is responsible for the regeneration of blood and immune cells and is maintained by bone marrow-resident hematopoietic stem and progenitor cells (HSPCs). Hematopoietic system is particularly susceptible to injury in response to genotoxic stress, resulting in the risk of bone marrow failure and secondary malignancies in cancer patients undergoing radiotherapy. Here we analyze the in vivo transcriptional response of HSPCs to genotoxic stress in a mouse whole-body irradiation model and, together with p53 ChIP-Seq and studies in p53-knockout (p53KO) mice, characterize the p53-dependent and p53-independent branches of this transcriptional response. Our work demonstrates the p53-independent induction of inflammatory transcriptional signatures in HSPCs in response to genotoxic stress and identifies multiple novel p53-target genes induced in HSPCs in response to whole-body irradiation. In particular, we establish the direct p53-mediated induction of P2X7 expression on HSCs and HSPCs in response to genotoxic stress. We further demonstrate the role of P2X7 in hematopoietic response to acute genotoxic stress, with P2X7 deficiency significantly extending mouse survival in irradiation-induced hematopoietic failure. We also demonstrate the role of P2X7 in the context of long-term HSC regenerative fitness following sublethal irradiation. Overall our studies provide important insights into the mechanisms of HSC response to genotoxic stress and further suggest P2X7 as a target for pharmacological modulation of HSC fitness and hematopoietic response to genotoxic injury.

scholarly journals TNFα Rescues Dendritic Cell Development in Hematopoietic Stem and Progenitor Cells Lacking C/EBPα

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1223
Author(s):  
Subramanian Anirudh ◽  
Angelika Rosenberger ◽  
Elke Schwarzenberger ◽  
Carolin Schaefer ◽  
Herbert Strobl ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Gene Expression Analysis ◽  
Hematopoietic Stem ◽  
Reporter Mouse ◽  
Multistep Process ◽  
Stem And Progenitor Cells ◽  
Culture Supernatants ◽  
Cytokine Profiling

Dendritic cells (DCs) are crucial effectors of the immune system, which are formed from hematopoietic stem and progenitor cells (HSPCs) by a multistep process regulated by cytokines and distinct transcriptional mechanisms. C/EBPα is an important myeloid transcription factor, but its role in DC formation is not well defined. Using a CebpaCre-EYFP reporter mouse model, we show that the majority of splenic conventional DCs are derived from Cebpa-expressing HSPCs. Furthermore, HSPCs isolated from Cebpa knockout (KO) mice exhibited a marked reduced ability to form mature DCs after in vitro culture with FLT3L. Differentiation analysis revealed that C/EBPα was needed for the formation of monocytic dendritic progenitors and their transition to common dendritic progenitors. Gene expression analysis and cytokine profiling of culture supernatants showed significant downregulation of inflammatory cytokines, including TNFα and IL-1β as well as distinct chemokines in KO HSPCs. In addition, TNFα-induced genes were among the most dysregulated genes in KO HSPCs. Intriguingly, supplementation of in vitro cultures with TNFα at least partially rescued DC formation of KO HSPCs, resulting in fully functional, mature DCs. In conclusion, these results reveal an important role of C/EBPα in early DC development, which in part can be substituted by the inflammatory cytokine TNFα.

scholarly journals The staying power of hematopoietic stem cells

2021 ◽  
Vol 220 (11) ◽  
Author(s):  
Michael L. Dustin
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Hematopoietic Stem ◽  
Cxcr4 Signaling ◽  
Stem And Progenitor Cells ◽  
Necessary And Sufficient

Hematopoietic stem and progenitor cells (HSPCs) use specialized adhesive structures referred to as magnupodium to stay in hematopoietic niches. Bessey et al. (2021. J. Cell Biol.https://doi.org/10.1083/jcb.202005085) define new characteristics of the magnupodium, including centriole polarization and the necessary and sufficient role of CXCR4 signaling.

scholarly journals Insufficiency of Non-Canonical PRC1 Complex Cooperates with an Activating JAK2 Mutation in the Pathogenesis of Myelofibrosis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 100-100
Author(s):  
Daisuke Shinoda ◽  
Yaeko Nakajima-Takagi ◽  
Motohiko Oshima ◽  
Atsunori Saraya ◽  
Hironori Harada ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Target Genes ◽  
Erythroid Differentiation ◽  
Gene Set Enrichment Analysis ◽  
Severe Thrombocytopenia ◽  
Promoter Regions ◽  
Hematopoietic Stem ◽  
Gene Set ◽  
Stem And Progenitor Cells

Abstract Introduction: PcG proteins form two main multiprotein complexes, Polycomb repressive complex 1 (PRC1) and PRC2. They repress the transcription of target genes. Polycomb group ring finger protein1 (PCGF1) is a component of PRC1.1, a non-canonical PRC1.1 that monoubiquitylates H2A at lysine 119 in a manner independent of H3K27me3. Several groups including ours showed that the loss of Ezh2, a component of PRC2, promotes the development of JAK2 V617F-induced Myelofibrosis (MF) in mice. However, the role of PRC1.1 in hematologic malignancies is still not fully understood. We found that the deletion of PCGF1 in mice promotes myeloid commitment of hematopoietic stem and progenitor cells (HSPCs), and eventually induces a lethal myeloproliferative neoplasm (MPN)-like disease in mice (Nakajima-Takagi Y, unpublished data). Based on these findings, we investigated the role of PCGF1 in a mouse model of JAK2V617F-induced myelofibrosis. Methods: We transplanted BM cells from Cre-ERT2, PCGF1flox/flox;Cre-ERT2, JAK2V617F;Cre-ERT2, and JAK2V617F;PCGF1flox/flox;Cre-ERT2 mice into lethally irradiated recipient mice. We deleted PCGF1 by tamoxifen administration 4 weeks after transplantation. Results: JAK2/PCGF1 KO mice developed lethal MF significantly earlier than the other genotypes (p<0.01). JAK2/PCGF1 KO mice showed progressive anemia and severe thrombocytopenia. Bone marrow analysis of JAK2/PCGF1 KO mice revealed a significant reduction in HSPCs and an increase in the number of granulocyte-macrophage progenitors (GMPs). Erythropoiesis was severely impaired at the later stages of erythroid differentiation. To understand the molecular basis of MF-initiating cells in JAK2/PCGF1 KO mouse, we performed a gene expression analysis of LSKs/GMPs/MEPs isolated from the primary recipients 1 month after TAM injection. Gene set enrichment analysis of RNA-seq data clearly showed de-repression of PRC1 target genes marked with H2AK119ub1 in hematopoietic stem and progenitor cells (HSPCs) from JAK2/PCGF1 KO mice. The gene set of megakaryocyte progenitors was also positively enriched in JAK2/PCGF1 KO HSPCs. ChIP sequencing of H2AK119Ub revealed that the levels of H2AK119Ub at promoter regions were mildly reduced in JAK2/PCGF1 KO LK cells compared with Pcgf1 KO LK cells. Among differentially expressed genes, we found that HoxA cluster genes were de-repressed in JAK2/PCGF1 KO progenitor cells including MEPs following significant reductions in H2AK119Ub levels at the promoter regions. Lin28b-Let-7-Hmga2 pathway genes that are activated in JAK2/Ezh2 KO progenitor cells were not altered in expression in JAK2/PCGF1 KO progenitor cells, suggesting different mechanisms operating in the pathogenesis of JAK2/Ezh2 KO and JAK2/PCGF1 KO MF. A selective AURKA inhibitor has been reported to promote differentiation of megakaryocytes with PMF-associated mutations and had potent antifibrotic and antitumor activity in vivo in mouse models of PMF (Wen et al., Nat Med 21:1473, 2015). Following this report, we treated JAK2/PCGF1 KO mice with JAK inhibitors and/or AURKA inhibitors. Both inhibitors improved MF-related phenotypes including impaired erythroid differentiation of JAK2/PCGF1 KO mice. Conclusions: Our findings suggest that dysregulated PRC1.1 function promotes JAK2V617F-induced MF with mechanisms distinct from MF associated with PRC2 dysfunction. Disclosures Harada: Celgene: Research Funding.

scholarly journals Developmental Stage and Sex-Specific Role of IGF/IGF1R Signaling in Hematopoietic Stem and Progenitor Cells

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1157-1157
Author(s):  
Ying Xie ◽  
Xin Hu ◽  
Zhe Li
Keyword(s):  
Developmental Stage ◽  
Progenitor Cells ◽  
Hematopoietic Cells ◽  
Conditional Knockout ◽  
Specific Role ◽  
Hematopoietic Stem ◽  
Male And Female ◽  
Stem And Progenitor Cells ◽  
Igf1r Signaling

Abstract Insulin-like growth factors (IGFs) are critical regulators of cell growth, proliferation and survival. Their activities are mainly mediated through insulin-like growth factor 1 receptor (IGF1R). Both IGFs and IGF1R are commonly involved in human cancers, including leukemia. Thus, a better understanding of the role of IGF/IGF1R signaling in normal hematopoiesis will enhance our understanding of leukemogenesis. We showed previously a developmental stage-specific role of this pathway in regulating fetal (but not adult) megakaryocytic progenitors via interplay with GATA1 (Genes Dev. 24:1659-72). To determine whether IGF/IGF1R signaling also plays differential roles in fetal and adult hematopoiesis in general, we analysed Igf1r conditional knockout mice using Mx1-Cre and Vav-Cre for the adult stage, and Tie2-Cre for the fetal stage. Although both fetal and adult stages of hematopoiesis were not significantly perturbed, loss of Igf1r in fetal (but not in adult) hematopoietic cells led to a significant reduction in the number of CFUs in clonogenic assays. In adult Igf1r -null Lin-Sca-1+c-Kit+ (LSK) hematopoietic stem and progenitor cells (HSPCs), analysis of the long-term hematopoietic stem cell (LT-HSC), short-term HSC (ST-HSC) and multipotent progenitor (MPP) subsets of LSK cells revealed an increase in the percentage of LT-HSCs when compared to that of wild-type (WT) mice, consistent with a recent study (Nature. 500:345-9). These data suggest that IGF/IGF1R signaling may have a developmental stage-restricted role in fetal progenitors; in adults, this pathway may play a role in the transition from LT-HSCs to MPPs. Recently it was shown that estrogen signaling plays an important role in regulating proliferation of HSCs (Nature. 505:555-8). Since during development, both male and female fetuses are exposed to the same high level of maternal estrogen, whereas in adults, male and female hematopoietic cells are exposed to different levels of circulating estrogen, we hypothesized that adult (but not fetal) HSPCs from male and female mice might exhibit different phenotypes in response to Igf1r -loss. To test this, we analysed the adult LSK population by separating males and females. Interestingly, we found that in females, but not in males, the LSK population is significantly reduced upon Igf1r -loss. Conversely, a preliminary study in fetal liver CFU assay revealed that both Igf1r -null female and male fetuses exhibited a similar reduction in their CFUs compared to matched WT controls. To understand the female-specific role of IGF/IGF1R signaling in adult HSPCs, we analysed the cell cycle status of HSCs. Similar to the reported observation (Nature. 505:555-8), we found that in WT female adults, there were significantly more Ki67+ cycling LT-HSCs than those in males. Intriguingly, Igf1r -loss significantly reduced the percentage of cycling LT-HSCs in females to a level comparable to that of WT males, but had a neglectable effect on cycling LT-HSCs in males. Administration of estradiol (E2) revealed that in females, E2 injection led to an increase in the percentage of Ki67+ LT-HSCs and this increase was partially abolished when under the Igf1r- null background; in males, E2 injection also increased the percentage of Ki67+ LT-HSCs, although we did not observe a notable reduction in this population when under the Igf1r -null background. Overall, our data suggest that although IGF/IGF1R signaling is not essential for normal hematopoiesis, it may play a more important role under conditions (e.g., fetal development, pregnancy) when there is a higher demand for the output from the hematopoietic system; in particular, this pathway may play an important role in mediating the effect of estrogen on self-renewal and proliferation of HSPCs. Disclosures No relevant conflicts of interest to declare.

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