scholarly journals Hapln1b, a central organizer of the extracellular matrix, modulates kit signalling to control developmental haematopoiesis

2021 ◽  
Author(s):  
Christopher B Mahony ◽  
Pietro Cacialli ◽  
Corentin Pasche ◽  
Rui Monteiro ◽  
Savvas N Savvides ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Computer Modelling ◽  
Fetal Liver ◽  
Early Embryo ◽  
Loss Of Function ◽  
Hemogenic Endothelium ◽  
Hematopoietic Tissue ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Functional Analyses

During early vertebrate development, hematopoietic stem and progenitor cells (HSPCs) are produced from hemogenic endothelium located in the dorsal aorta, before they migrate to a transient niche where they expand, the fetal liver and the caudal hematopoietic tissue (CHT), in mammals and zebrafish, respectively. In zebrafish, previous studies have shown that the extracellular matrix (ECM) around the aorta needs to be degraded to allow HSPCs to leave the aortic floor and reach blood circulation. However, the role of the ECM components in HSPC specification has never been addressed. We show here that hapln1b, a key component of the ECM is specifically expressed in hematopoietic sites in the zebrafish embryo. Gain- and loss-of-function experiments all resulted in the absence of HSPCs in the early embryo, showing that hapln1b is required, at the correct level, to specify HSPCs in the hemogenic endothelium. Furthermore, we show that the expression of hapln1b is necessary to maintain the integrity of the ECM through its link domain. By combining functional analyses and computer modelling, we show that kitlgb interacts with the ECM to specify HSPCs. We demonstrate that the ECM is an integral component of the microenvironment and mediates cytokine signalling that is required for HSPC specification.

scholarly journals Hapln1b organizes the ECM to modulate kit signaling and control developmental hematopoiesis in zebrafish

2020 ◽  
Author(s):  
Christopher B. Mahony ◽  
Corentin Pasche ◽  
Vincent Braunersreuther ◽  
Savvas N. Savvides ◽  
Ariane de Agostini ◽  
...  
Keyword(s):  
Computer Modelling ◽  
Fetal Liver ◽  
Early Embryo ◽  
Cytokine Signaling ◽  
Loss Of Function ◽  
Hemogenic Endothelium ◽  
Hematopoietic Tissue ◽  
Hematopoietic Stem ◽  
Functional Analyses ◽  
And Control

AbstractDuring early vertebrate development, hematopoietic stem cells (HSCs) are produced from a hemogenic endothelium located in the dorsal aorta, before they migrate to a transient niche where they expand, the fetal liver and the caudal hematopoietic tissue (CHT), in mammals and zebrafish, respectively. In zebrafish, previous studies have shown that the extracellular matrix (ECM) around the aorta needs to be degraded to allow HSCs to leave the aortic floor and reach blood circulation. However, the role of the ECM components in HSC specification has never been addressed. We show here that hapln1b, a key component of the ECM is specifically expressed in hematopoietic sites in the zebrafish embryo. Gain- and loss-of-function experiments all resulted in the absence of HSCs in the early embryo, showing that hapln1b is required, at the correct level, to specify HSCs in the hemogenic endothelium. Furthermore, we show that the expression of hapln1b is necessary to maintain the integrity of the ECM through its link domain. In addition, by combining functional analyses and computer modelling, we show that kitlgb interacts with the ECM, to specify HSCs. Overall, we have demonstrated that the ECM is an integral component of the microenvironment as it mediates specific cytokine signaling that is required for normal HSC specification.

scholarly journals Targeted disruption of Zfp36l2, encoding a CCCH tandem zinc finger RNA-binding protein, results in defective hematopoiesis

Blood ◽  
2009 ◽  
Vol 114 (12) ◽  
pp. 2401-2410 ◽  
Author(s):  
Deborah J. Stumpo ◽  
Hal E. Broxmeyer ◽  
Toni Ward ◽  
Scott Cooper ◽  
Giao Hangoc ◽  
...  
Keyword(s):  
Rna Binding ◽  
Fetal Liver ◽  
Early Embryo ◽  
Hematopoietic Progenitors ◽  
Targeted Disruption ◽  
Hematopoietic Stem ◽  
Subsequent Degradation ◽  
Stem And Progenitor Cells ◽  
Partial Deficiency ◽  
Definitive Hematopoiesis

Abstract Members of the tristetraprolin family of tandem CCCH finger proteins can bind to AU-rich elements in the 3′-untranslated region of mRNAs, leading to their deadenylation and subsequent degradation. Partial deficiency of 1 of the 4 mouse tristetraprolin family members, Zfp36l2, resulted in complete female infertility because of early embryo death. We have now generated mice completely deficient in the ZFP36L2 protein. Homozygous Zfp36l2 knockout (KO) mice died within approximately 2 weeks of birth, apparently from intestinal or other hemorrhage. Analysis of peripheral blood from KO mice showed a decrease in red and white cells, hemoglobin, hematocrit, and platelets. Yolk sacs from embryonic day 11.5 (E11.5) Zfp36l2 KO mice and fetal livers from E14.5 KO mice gave rise to markedly reduced numbers of definitive multilineage and lineage-committed hematopoietic progenitors. Competitive reconstitution experiments demonstrated that Zfp36l2 KO fetal liver hematopoietic stem cells were unable to adequately reconstitute the hematopoietic system of lethally irradiated recipients. These data establish Zfp36l2 as a critical modulator of definitive hematopoiesis and suggest a novel regulatory pathway involving control of mRNA stability in the life cycle of hematopoietic stem and progenitor cells.

scholarly journals A connexin/ifi30 pathway bridges HSCs with their niche to dampen oxidative stress

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pietro Cacialli ◽  
Christopher B. Mahony ◽  
Tim Petzold ◽  
Patrizia Bordignon ◽  
Anne-Laure Rougemont ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
Oxygen Species ◽  
Oxidized Glutathione ◽  
Hematopoietic Tissue ◽  
Hematopoietic Stem ◽  
Tissue Equivalent ◽  
Stem And Progenitor Cells ◽  
Hematopoietic Niche

AbstractReactive oxygen species (ROS) represent a by-product of metabolism and their excess is toxic for hematopoietic stem and progenitor cells (HSPCs). During embryogenesis, a small number of HSPCs are produced from the hemogenic endothelium, before they colonize a transient organ where they expand, for example the fetal liver in mammals. In this study, we use zebrafish to understand the molecular mechanisms that are important in the caudal hematopoietic tissue (equivalent to the mammalian fetal liver) to promote HSPC expansion. High levels of ROS are deleterious for HSPCs in this niche, however this is rescued by addition of antioxidants. We show that Cx41.8 is important to lower ROS levels in HSPCs. We also demonstrate a new role for ifi30, known to be involved in the immune response. In the hematopoietic niche, Ifi30 can recycle oxidized glutathione to allow HSPCs to dampen their levels of ROS, a role that could be conserved in human fetal liver.

scholarly journals WNT5A from the fetal liver vascular niche supports human fetal liver hematopoiesis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yoon Jung Choi ◽  
Adam M. Heck ◽  
Brian J. Hayes ◽  
Daniel Lih ◽  
Samuel G. Rayner ◽  
...  
Keyword(s):  
Fetal Liver ◽  
Loss Of Function ◽  
Hematopoietic Stem ◽  
Human Fetal Liver ◽  
Supportive Role ◽  
Organ Specific ◽  
Stem And Progenitor Cells ◽  
Critical Organ ◽  
Insight Into

AbstractThe human fetal liver is a critical organ for prenatal hematopoiesis, the study of which offers insights into niche signals that regulate the fates of hematopoietic stem and progenitor cells (HSPCs) during fetal development. Here, we demonstrate that human fetal liver endothelium uniquely supports the maturation and expansion of multilineage HSPCs. Specifically, co-culture of fetal liver-derived immature CD43+CD45− hematopoietic cells with human fetal liver endothelial cells (ECs) led to a profound increase in the numbers of phenotypic CD45+CD34+ HSPCs and multilineage colony-forming progenitors generated in vitro, when compared to co-culture with ECs derived from other organs. We further identified a supportive role for EC-derived WNT5A in this process via gain- and loss-of-function studies within ECs. Our study emphasizes the importance of the organ-specific endothelial niche in supporting hematopoietic development and provides novel insight into signals that may facilitate HSPC expansion in vitro for clinical applications.

scholarly journals Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3197-3207 ◽  
Author(s):  
Kirsteen J. Campbell ◽  
Mary L. Bath ◽  
Marian L. Turner ◽  
Cassandra J. Vandenberg ◽  
Philippe Bouillet ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Fetal Liver ◽  
Cytotoxic Agents ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Fetal Liver Cells ◽  
Follicular Lymphomas ◽  
The Impact

Abstract Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eμ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eμ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.

Distinct roles of integrins α6 and α4 in homing of fetal liver hematopoietic stem and progenitor cells

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2399-2407 ◽  
Author(s):  
Hong Qian ◽  
Elisabeth Georges-Labouesse ◽  
Alexander Nyström ◽  
Anna Domogatskaya ◽  
Karl Tryggvason ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Fetal Liver ◽  
Integrin Receptors ◽  
Hematopoietic Stem ◽  
Blocking Antibody ◽  
Stem And Progenitor Cells ◽  
Integrin Α4 ◽  
And Function ◽  
Blocking Antibodies

Homing of hematopoietic stem cells (HSCs) into the bone marrow (BM) is a prerequisite for establishment of hematopoiesis during development and following transplantation. However, the molecular interactions that control homing of HSCs, in particular, of fetal HSCs, are not well understood. Herein, we studied the role of the α6 and α4 integrin receptors for homing and engraftment of fetal liver (FL) HSCs and hematopoietic progenitor cells (HPCs) to adult BM by using integrin α6 gene–deleted mice and function-blocking antibodies. Both integrins were ubiquitously expressed in FL Lin−Sca-1+Kit+ (LSK) cells. Deletion of integrin α6 receptor or inhibition by a function-blocking antibody inhibited FL LSK cell adhesion to its extracellular ligands, laminins-411 and -511 in vitro, and significantly reduced homing of HPCs to BM. In contrast, the anti-integrin α6 antibody did not inhibit BM homing of HSCs. In agreement with this, integrin α6 gene–deleted FL HSCs did not display any homing or engraftment defect compared with wild-type littermates. In contrast, inhibition of integrin α4 receptor by a function-blocking antibody virtually abrogated homing of both FL HSCs and HPCs to BM, indicating distinct functions for integrin α6 and α4 receptors during homing of fetal HSCs and HPCs.

Integrin alpha 6 Is Essential for Fetal Hematopoietic Progenitor, but Not Fetal Stem Cell Homing to Bone Marrow.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1387-1387
Author(s):  
Hong Qian ◽  
Sten Eirik W. Jacobsen ◽  
Marja Ekblom
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Fetal Liver ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Integrin Alpha 6

Abstract Homing of transplanted hematopoietic stem cells (HSC) in the bone marrow (BM) is a prerequisite for establishment of hematopoiesis following transplantation. However, although multiple adhesive interactions of HSCs with BM microenviroment are thought to critically influence their homing and subsequently their engraftment, the molecular pathways that control the homing of transplanted HSCs, in particular, of fetal HSCs are still not well understood. In experimental mouse stem cell transplantation models, several integrins have been shown to be involved in the homing and engraftment of both adult and fetal stem and progenitor cells in BM. We have previously found that integrin a6 mediates human hematopoietic stem and progenitor cell adhesion to and migration on its specific ligands, laminin-8 and laminin-10/11 in vitro (Gu et al, Blood, 2003; 101:877). Furthermore, integrin a6 is required for adult mouse HSC homing to BM in vivo (Qian et al., Abstract American Society of Hematology, Blood 2004 ). We have now found that the integrin a6 chain like in adult HSC is ubiquitously (>99%) expressed also in fetal liver hematopoietic stem and progenitor cells (lin−Sca-1+c-Kit+, LSK ). In vitro, fetal liver LSK cells adhere to laminin-10/11 and laminin-8 in an integrin a6b1 receptor-dependent manner, as shown by function blocking monoclonal antibodies. We have now used a function blocking monoclonal antibody (GoH3) against integrin a6 to analyse the role of the integrin a6 receptor for the in vivo homing of fetal liver hematopoietic stem and progenitor cells to BM. The integrin a6 antibody inhibited homing of fetal liver progenitors (CFU-C) into BM of lethally irradiated recipients. The number of homed CFU-C in BM was reduced by about 40% as compared to the cells incubated with an isotype matched control antibody. To study homing of long-term repopulating stem cells, BM cells were first incubated with anti-integrin alpha 6 or anti-integrin alpha 4 or control antibody, and then injected intravenously into lethally irradiated primary recipients. After three hours, BM cells of the primary recipients were analysed by competitive repopulation assay in secondary recipients. Blood analysis up to 16 weeks after transplantation showed that no reduction of stem cell reconstitution from integrin a6 antibody treated cells as compared to cells treated with control antibody. In accordance with this, fetal liver HSC from integrin a6 gene deleted embryos did not show any impairment of homing and engraftment in BM as compared to normal littermates. These results suggest that integrin a6 plays an important developmentally regulated role for homing of distinct hematopoietic stem and progenitor cell populations in vivo.

In utero transplantation of fetal liver cells in the mucopolysaccharidosis type VII mouse results in low-level chimerism, but overexpression of β-glucuronidase can delay onset of clinical signs

Blood ◽  
2001 ◽  
Vol 97 (6) ◽  
pp. 1625-1634 ◽  
Author(s):  
Margret L. Casal ◽  
John H. Wolfe
Keyword(s):  
Stem Cells ◽  
Gene Transfer ◽  
Progenitor Cells ◽  
Fetal Liver ◽  
Retroviral Vector ◽  
In Utero ◽  
Hematopoietic Stem ◽  
Donor Cells ◽  
Stem And Progenitor Cells ◽  
Mps Vii

Mice with the lysosomal storage disease mucopolysaccharidosis (MPS) VII, caused by a deficiency of β-glucuronidase (GUSB), have signs of disease present at birth. Bone marrow transplantation (BMT) or retroviral vector–mediated gene transfer into hematopoietic stem cells can partially correct the disease in adult mice, and BMT performed at birth results in a better clinical outcome. Thus, treatment in utero may result in further improvement. However, this must be done without cyto-ablation, and the donor cells do not have a competitive repopulating advantage over host cells. Transplantation in utero of either syngeneic fetal liver hematopoietic stem cells marked with a retroviral vector, or allogeneic donor cells that constitutively express high levels of human GUSB from a transgene, resulted in only about 0.1% engraftment in the adult. Immuno-affinity enrichment of stem and progenitor cells of 5- to 10-fold resulted in significantly higher GUSB activities at 2 months of age, but by 6 months engraftment was about 0.1%. Attempts to further increase the number of stem and progenitor cells were deleterious to the recipients. Nevertheless, GUSB expressed during the first 2 months of life in MPS VII fetuses could delay the onset of overt signs of disease. This suggests that the expression of some normal enzyme activity beginning in fetal life may offer the possibility of slowing the progression of the disease until more definitive postnatal transplantation or gene transfer to stem cells could be accomplished.

scholarly journals Extracellular vesicles of stromal origin target and support hematopoietic stem and progenitor cells

2017 ◽  
Vol 216 (7) ◽  
pp. 2217-2230 ◽  
Author(s):  
Gregoire Stik ◽  
Simon Crequit ◽  
Laurence Petit ◽  
Jennifer Durant ◽  
Pierre Charbord ◽  
...  
Keyword(s):  
Gene Expression ◽  
Progenitor Cells ◽  
Extracellular Vesicles ◽  
Ex Vivo ◽  
Fetal Liver ◽  
Critical Role ◽  
Molecular Signature ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells

Extracellular vesicles (EVs) have been recently reported as crucial mediators in cell-to-cell communication in development and disease. In this study, we investigate whether mesenchymal stromal cells that constitute a supportive microenvironment for hematopoietic stem and progenitor cells (HSPCs) released EVs that could affect the gene expression and function of HSPCs. By taking advantage of two fetal liver–derived stromal lines with widely differing abilities to maintain HSPCs ex vivo, we demonstrate that stromal EVs play a critical role in the regulation of HSPCs. Both supportive and nonsupportive stromal lines secreted EVs, but only those delivered by the supportive line were taken up by HSPCs ex vivo and in vivo. These EVs harbored a specific molecular signature, modulated the gene expression in HSPCs after uptake, and maintained the survival and clonogenic potential of HSPCs, presumably by preventing apoptosis. In conclusion, our study reveals that EVs are an important component of the HSPC niche, which may have major applications in regenerative medicine.

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