Abstract 13: Plasminogen Is Required for Hematopoietic Stem Cell-Mediated Cardiac Repair After Myocardial Infarction

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Yanqing Gong ◽  
Jane Hoover-Plow ◽  
Ying Li
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Tissue Repair ◽  
Critical Role ◽  
Cardiac Repair ◽  
Internal Diameter ◽  
Hematopoietic Stem

Ischemic heart disease, including myocardial infarction (MI), is the primary cause of death throughout the US. Granulocyte colony-stimulating factor (G-CSF) is used to mobilize hematopoietic progenitor and stem cells (HPSC) to improve cardiac recovery after MI. However, poor-mobilization to G-CSF is observed in 25% of patients and 10-20% of healthy donors. Therefore, a better understanding of the underlying mechanisms regulating G-CSF-induced cardiac repair may offer novel approaches for strengthening stem cell-mediated therapeutics. Our previous studies have identified an essential role of Plg in HPSC mobilization from bone marrow (BM) in response to G-CSF. Here, we investigate the role of Plg in G-CSF-stimulated cardiac repair after MI. Our data show that G-CSF significantly improves cardiac tissue repair including increasing neovascularization in the infarct area, and improving ejection fraction and LV internal diameter by echocardiogram in wild-type mice. No improvement in tissue repair and heart function by G-CSF is observed in Plg -/- mice, indicating that Plg is required for G-CSF-regulated cardiac repair after MI. To investigate whether Plg regulates HPSC recruitment to ischemia area, bone marrow transplantion (BMT) with EGFP-expressing BM cells was performed to visualize BM-derived stem cells in infarcted tissue. Our data show that G-CSF dramatically increases recruitment of GFP+ cells (by 16 fold) in WT mice but not in Plg -/- mice, suggesting that Plg is essential for HPSC recruitment from BM to the lesion sites after MI. In further studies, we investigated the role of Plg in the regulation of SDF-1/CXCR-4 axis, a major regulator for HPSC recruitment. Our results show that G-CSF significantly increases CXCR-4 expression in infarcted area in WT mice. While G-CSF-induced CXCR-4 expression is markedly decreased (80%) in Plg -/- mice, suggesting Plg may regulate CXCR-4 expression during HSPC recruitment to injured heart. Interestingly, Plg does not affect SDF-1 expression in response to G-CSF treatment. Taken together, our findings have identified a critical role of Plg in HSPC recruitment to the lesion site and subsequent tissue repair after MI. Thus, targeting Plg may offer a new therapeutic strategy to improve G-CSF-mediated cardiac repair after MI.

Abstract 197: Plasminogen Is Required for Hematopoietic Stem Cell-Mediated Cardiac Repair After Myocardial Infarction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yanqing Gong ◽  
Ying Li ◽  
Jane Hoover-Plow
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Stem Cell ◽  
Heart Function ◽  
Critical Role ◽  
The United States ◽  
Cardiac Repair ◽  
Internal Diameter ◽  
Hematopoietic Stem

Myocardial infarction (MI) is the primary cause of death throughout the United States. Granulocyte colony-stimulating factor (G-CSF) is used to mobilize hematopoietic progenitor and stem cells (HPSC) to improve cardiac recovery after MI. However, poor-mobilization to G-CSF is observed in 25% of patients and 10-20% of healthy donors. Therefore, a better understanding of the underlying mechanisms may offer novel approaches for G-CSF-mediated therapeutics. Our previous studies have identified an essential role of Plg in HPSC mobilization from bone marrow (BM) in response to G-CSF. Here, we investigate the role of Plg in G-CSF-stimulated cardiac repair after MI. Our data show that G-CSF significantly improves cardiac repair including increasing neovascularization in the infarct area, and improving ejection fraction and LV internal diameter determined by echocardiogram in WT mice. No improvement on heart function is observed in Plg -/- mice, indicating Plg is required for G-CSF-regulated cardiac repair after MI. To investigate whether Plg regulates HPSC recruitment to the ischemic area, BM transplantation with EGFP-expressing BM cells was performed to visualize BM-derived stem cells in infarcted tissue. Our data show that G-CSF dramatically increases recruitment of GFP + cKit + cells (by 12 fold) in WT mice but not in Plg -/- mice. In addition, BM stem cell-derived vessels and arteries are infrequent in Plg -/- mice suggesting that Plg enhances cardiac repair by promoting stem cell recruitment to the lesion. In further studies, we investigated the role of Plg in the regulation of SDF-1/CXCR-4 axis, a major regulator for HPSC recruitment. Our results show that G-CSF significantly increases CXCR-4 expression in the infarcted area in WT mice. While G-CSF-induced CXCR-4 expression is markedly decreased (80%) in Plg -/- mice, suggesting Plg may regulate CXCR-4 expression during HSPC recruitment to injured heart. Interestingly, Plg does not affect SDF-1 expression in response to G-CSF treatment. Taken together, our findings have identified a critical role of Plg in HSPC recruitment to the lesion site and subsequent tissue repair after MI. Thus, targeting Plg may offer a new therapeutic strategy to improve G-CSF-mediated cardiac repair after MI.

scholarly journals The Role of the Bone Marrow Microenvironment in the Response to Infection

2020 ◽  
Vol 11 ◽  
Author(s):  
Courtney B. Johnson ◽  
Jizhou Zhang ◽  
Daniel Lucas
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Immune Cells ◽  
Critical Role ◽  
Primary Source ◽  
Bone Marrow Microenvironment ◽  
Future Research ◽  
Multipotent Stem Cells ◽  
Hematopoietic Stem

Hematopoiesis in the bone marrow (BM) is the primary source of immune cells. Hematopoiesis is regulated by a diverse cellular microenvironment that supports stepwise differentiation of multipotent stem cells and progenitors into mature blood cells. Blood cell production is not static and the bone marrow has evolved to sense and respond to infection by rapidly generating immune cells that are quickly released into the circulation to replenish those that are consumed in the periphery. Unfortunately, infection also has deleterious effects injuring hematopoietic stem cells (HSC), inefficient hematopoiesis, and remodeling and destruction of the microenvironment. Despite its central role in immunity, the role of the microenvironment in the response to infection has not been systematically investigated. Here we summarize the key experimental evidence demonstrating a critical role of the bone marrow microenvironment in orchestrating the bone marrow response to infection and discuss areas of future research.

Differential Role for VLA-5 in Mobilization of Heamotopoieic Stem Cells Toward Peripheral Blood and Homing to Bone Marrow and Spleen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2190-2190 ◽  
Author(s):  
Pieter K. Wierenga ◽  
Ellen Weersing ◽  
Bert Dontje ◽  
Gerald de Haan ◽  
Ronald P. van Os
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Late Antigen ◽  
Cell Mobilization

Abstract Adhesion molecules have been implicated in the interactions of hematopoietic stem and progenitor cells with the bone marrow extracellular matrix and stromal cells. In this study we examined the role of very late antigen-5 (VLA-5) in the process of stem cell mobilization and homing after stem cell transplantation. In normal bone marrow (BM) from CBA/H mice 79±3 % of the cells in the lineage negative fraction express VLA-5. After mobilization with cyclophosphamide/G-CSF, the number of VLA-5 expressing cells in mobilized peripheral blood cells (MPB) decreases to 36±4%. The lineage negative fraction of MPB cells migrating in vitro towards SDF-1α (M-MPB) demonstrated a further decrease to 3±1% of VLA-5 expressing cells. These data are suggestive for a downregulation of VLA-5 on hematopoietic cells during mobilization. Next, MPB cells were labelled with PKH67-GL and transplanted in lethally irradiated recipients. Three hours after transplantation an increase in VLA-5 expressing cells was observed which remained stable until 24 hours post-transplant. When MPB cells were used the percentage PKH-67GL+ Lin− VLA-5+ cells increased from 36% to 88±4%. In the case of M-MPB cells the number increased from 3% to 33±5%. Although the increase might implicate an upregulation of VLA-5, we could not exclude selective homing of VLA-5+ cells as a possible explanation. Moreover, we determined the percentage of VLA-5 expressing cells immediately after transplantation in the peripheral blood of the recipients and were not able to observe any increase in VLA-5+ cells in the first three hours post-tranpslant. Finally, we separated the MPB cells in VLA-5+ and VLA-5− cells and plated these cells out in clonogenic assays for progenitor (CFU-GM) and stem cells (CAFC-day35). It could be demonstared that 98.8±0.5% of the progenitor cells and 99.4±0.7% of the stem cells were present in the VLA-5+ fraction. Hence, VLA-5 is not downregulated during the process of mobilization and the observed increase in VLA-5 expressing cells after transplantation is indeed caused by selective homing of VLA-5+ cells. To shed more light on the role of VLA-5 in the process of homing, BM and MPB cells were treated with an antibody to VLA-5. After VLA-5 blocking of MPB cells an inhibition of 59±7% in the homing of progenitor cells in bone marrow could be found, whereas homing of these subsets in the spleen of the recipients was only inhibited by 11±4%. For BM cells an inhibition of 60±12% in the bone marrow was observed. Homing of BM cells in the spleen was not affected at all after VLA-5 blocking. Based on these data we conclude that mobilization of hematopoietic progenitor/stem cells does not coincide with a downregulation of VLA-5. The observed increase in VLA-5 expressing cells after transplantation is caused by preferential homing of VLA-5+ cells. Homing of progenitor/stem cells to the bone marrow after transplantation apparantly requires adhesion interactions that can be inhibited by blocking VLA-5 expression. Homing to the spleen seems to be independent of VLA-5 expression. These data are indicative for different adhesive pathways in the process of homing to bone marrow or spleen.

scholarly journals Adaptation of Marrow Osteoblast Morphology Mediated By a Hematopoietic-Derived Endosteal Cell Is Critical for Donor HSC Engraftment after BMT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3603-3603 ◽  
Author(s):  
Kathleen Overholt ◽  
Satoru Otsuru ◽  
Victoria Best ◽  
Adam Guess ◽  
Timothy S. Olson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Diphtheria Toxin ◽  
Fluorescent Protein ◽  
Critical Role ◽  
Hematopoietic Cells ◽  
Hematopoietic Stem ◽  
Cell Engraftment

Abstract Hematopoietic stem cells reside in the bone marrow within specialized microenvironments designated the stem cell niche. The remarkable advances over the past decade have dramatically enhanced our perception of the niche; yet, the operative mechanisms after radioablation in preparation for bone marrow transplantation (BMT) remain poorly understood. We have previously described a profound remodeling of the bone marrow architecture after total body irradiation (TBI). This remodeling, comprised of enlarged, proliferating marrow osteoblasts and megakaryocyte migration from the central marrow space to the endosteal surface, is essential for efficient engraftment of donor cells after BMT; hence, marrow remodeling seems to represent an adaptation of the endosteal niche. To investigate whether hematopoietic cells regulate these changes, we sought to deplete all hematopoietic cells prior to TBI. We generated mice expressing the diphtheria toxin receptor (DTR) in all CD45-derived cells using the Cre/loxP model. To validate this strategy, we first crossed CD45Cre mice, where cre is expressed under the control of the endogenous promoter, with Z/RED mice which will then irreversibly express red fluorescent protein (RFP) in all cells that were derived from CD45-expressing progenitors. Surprisingly, we identified a population of RFP-expressing cells residing among osteoblasts along the endosteal and trabecular bone surfaces (designated red Bone Lining Cell, red BLC). By immunofluorescence staining, these cells lacked expression of CD45, lineage markers (Gr1, CD11b, F 4/80, CD3, B220, Ter119), and cathepsin K indicating it is not a hematopoietic cell, specifically not an osteal macrophage or osteoclast, but was unequivocally derived from CD45-expressing progenitors. We reproduced this fate map by crossing vav1Cre mice with Z/RED mice, confirming the identification and hematopoietic lineage of the red BLC. When crossed with Col2.3GFP transgenic mice, which express green fluorescent protein (GFP) in mature osteoblasts, red BLCs lacked GFP co-expression indicating it is not a generic osteoblast. Interestingly, after TBI, red BLCs markedly proliferate, but do not enlarge, in the metaphysis and epiphysis, but not in the diaphysis, coincident with the osteoblast proliferation suggesting a possible role in marrow remodeling. To pursue our original hypothesis that hematopoietic cells may regulate marrow remodeling, we treated mice expressing DTR in all CD45-derived cells and their non-expressing littermates (controls) with diphtheria toxin (DT) followed by TBI to induce marrow remodeling without the effect of CD45-derived cells. Marrow remodeling ensued; however, the characteristically enlarged endosteal osteoblasts adopted a strikingly flattened morphology (cell thickness, 8.45±0.31 vs. 3.42±0.11 μm, P<0.0001). We then used our competitive secondary transplantation assay to assess engraftment of long-term hematopoietic stem cells (HSCs) in primary recipients. Only 1 of 15 CD45-cell depleted mice engrafted HSCs compared to 10 of 15 control mice (P=0.0017) indicating a critical role of osteoblast morphology, governed by a CD45-derived cell, for donor stem cell engraftment in BMT. Megakaryocytes (Mks) and monocytes/macrophages (MMs) are the two marrow hematopoietic lineages that are recognized to survive short term after TBI and we have shown that the CD45-derived red BLC survives and proliferates after TBI. To determine if these cells regulate osteoblasts, we depleted Mks by treating Mk-specific DTR-expressing mice (generated with PF4Cre mice) with DT (>95%), and in separate cohort, MMs using clondronate (>95%). In each cohort, post-TBI marrow remodeling included the expected enlarged endosteal osteoblasts indistinguishable from controls, suggesting that neither Mks nor MMs direct the acquired osteoblast morphology. Collectively, our data indicate that enlarging of endosteal osteoblasts after marrow ablation is critical for donor cell engraftment, possibly due to altered adhesive properties for primitive hematopoietic cells. During post-TBI marrow remodeling, a CD45-derived cell that survives radioablation governs this osteoblast morphology. Our data implicate the red BLC as this key regulatory element. Understanding the red BLC will likely offer new insight into the niche and may lead to novel strategies to enhance HSC engraftment in BMT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Megakaryopoiesis and Platelet Biology: Roles of Transcription Factors and Emerging Clinical Implications

2021 ◽  
Vol 22 (17) ◽  
pp. 9615
Author(s):  
Ji-Yoon Noh
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Transcription Factors ◽  
Blood Cells ◽  
Thrombus Formation ◽  
Critical Role ◽  
Clinical Implications ◽  
Disease Development ◽  
Hematopoietic Stem

Platelets play a critical role in hemostasis and thrombus formation. Platelets are small, anucleate, and short-lived blood cells that are produced by the large, polyploid, and hematopoietic stem cell (HSC)-derived megakaryocytes in bone marrow. Approximately 3000 platelets are released from one megakaryocyte, and thus, it is important to understand the physiologically relevant mechanism of development of mature megakaryocytes. Many genes, including several key transcription factors, have been shown to be crucial for platelet biogenesis. Mutations in these genes can perturb megakaryopoiesis or thrombopoiesis, resulting in thrombocytopenia. Metabolic changes owing to inflammation, ageing, or diseases such as cancer, in which platelets play crucial roles in disease development, can also affect platelet biogenesis. In this review, I describe the characteristics of platelets and megakaryocytes in terms of their differentiation processes. The role of several critical transcription factors have been discussed to better understand the changes in platelet biogenesis that occur during disease or ageing.

Lysophospholipids synergistically promote primitive hematopoietic cell chemotaxis via a mechanism involving Vav 1

Blood ◽  
2003 ◽  
Vol 102 (8) ◽  
pp. 2798-2802 ◽  
Author(s):  
Anthony D. Whetton ◽  
Yuning Lu ◽  
Andrew Pierce ◽  
Louise Carney ◽  
Elaine Spooncer
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Biology ◽  
Critical Role ◽  
Hematopoietic Cell ◽  
Cell Trafficking ◽  
Hematopoietic Stem ◽  
Stem Cell Trafficking ◽  
Cell Chemotaxis

Abstract Hematopoiesis is sustained by the proliferation and development of an extremely low number of hematopoietic stem cells resident in the bone marrow. These stem cells can migrate from their bone marrow microenvironment and can be found at low levels in the peripheral blood. The factors that regulate egress or ingress of the stem cells from the marrow include cytokines and chemokines. This process of stem cell trafficking is fundamental to both stem cell biology and stem cell transplantation. We show that primitive hematopoietic cells with cobblestone area–forming cell activity express receptors for and display enhanced motility in response to a new class of stem cell agonists, namely lysophospholipids. These agents synergistically promote chemokinestimulated cell chemotaxis, a process that is crucial in stem cell homing. The response to lysophospholipids is mediated by Rac, Rho, and Cdc42 G proteins and the hematopoietic-specific guanyl nucleotide exchange factor Vav 1. Inhibitor studies also show a critical role for phosphatidylinositol 3 kinase (PI3K). Lipid mediators, therefore, regulate the critical process of primitive hematopoietic cell motility via a PI3K- and Vav-dependent mechanism and may govern stem cell movement in vivo. These results are of relevance to understanding stem cell trafficking during bone marrow transplantation.

CXCR4-SDF-1 Signaling Mediated up-Regulation of Survivin Expression In Mesenchymal Progenitor Cells Is Critical for Their Proliferation and Maintenance of Osteoblastic Niche

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 941-941
Author(s):  
Pratibha Singh ◽  
Jennifer Speth ◽  
Peirong Hu ◽  
Louis M. Pelus
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Survivin Expression ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Cxcr4 Signaling

Abstract Abstract 941 Hematopoietic stem cells reside in osteoblastic and vascular niches within the bone marrow. The osteoblastic niche is composed of mesenchymal stem cell derived progenitor cells (MPC) and osteoblasts and are the main sources of the CXC chemokine CXCL12/SDF-1 in the bone marrow microenvironment. Several published studies suggest that the interaction between CXCR4 expressed on hematopoietic stem cells with SDF-1 produced in the bone marrow microenvironment is important for their retention in the bone-marrow. However, the role of SDF-CXCR4 signaling in formation and maintenance of osteoblastic niches in the bone marrow is not known. In this study, we examined the role of CXCR4 signaling in MPC proliferation and differentiation and its effects on hematopoietic stem cell (HSC) function. Flow cytometry analysis demonstrated that CXCR4 is expressed on the phenotypically defined MPC. Deletion of CXCR4 in tamoxifen cre inducible CXCR4flox-flox mice (verified by PCR and flow cytometry; 90% gene deletion and surface CXCR4 expression) results in significantly decreased numbers of Lin- CD45- CD31- Sca-1+ ALCAM- MPC (39±4.2%) and Lin- CD45- CD31- Sca-1-CD51+ osteoblasts (25±2.6%) in bone marrow 15 days after tamoxifen treatment. SDF-1 induced proliferation of CXCR4 deficient MPC was decreased by 4-fold compared to control, measured by the colony forming unit-fibroblast (CFU-F) assay. To determine, whether CXCR4 deficiency in bone marrow stromal cells affects SDF-1 induced HSC proliferation, we cultured FACS sorted wild-type SLAM SKL (103 cells) on CXCR4 deficient stroma for 5 days and total SLAM SKL cell numbers were counted by flow-cytometey analysis. CXCR4 deficient stroma failed to support optimal HSC proliferation and 48±5.2% less SLAM KSL cells was observed on CXCR4 deficient stroma compared to wild-type stroma. To investigate the mechanisms through which CXCR4-SDF-1 signaling regulates MPC proliferation, we evaluated the effect of SDF-1 treatment on expression of the anti-apoptotic and cell-cycle regulator protein, Survivin, in MPC. Multivariate intracellular flow cytometry demonstrated that Survivin expression increased by 23±4.2% in wild-type MPC after SDF-1 treatment (50ng/ml), however no significant increased was demonstrated in CXCR4 deficient MPC cells. CFU-F formation was reduced by 2.5 fold when the Survivin gene was conditionally deleted in MPC. Moreover, fewer SLAM SKL cells were detected on Survivin deficient stroma compared to wild-type stroma after SDF-1 treatment for 5 days. In conclusion, our data suggest that CXCR4-SDF-1 signaling mediated Survivin expression in MPC is important for their proliferation and maintenance of the bone-marrow hematopoietic niche. Disclosures: No relevant conflicts of interest to declare.

Critical Role Of Jak2 In The Maintenance and Function Of Adult Hematopoietic Stem Cells

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1180-1180
Author(s):  
Hajime Akada ◽  
Saeko Akada ◽  
Golam Mohi
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Critical Role ◽  
Receptor Protein ◽  
Specific Gene ◽  
Hematopoietic Stem ◽  
And Function

Abstract Hematopoietic stem cells (HSCs) play an essential role in the long-term maintenance of hematopoiesis. Various intracellular signaling proteins, transcription factors and extracellular matrix proteins contribute to the maintenance and function of HSCs. Jak2, a member of the Janus family of non-receptor protein tyrosine kinases, is activated in response to a variety of cytokines. It has been shown that germ-line deletion of Jak2 results in embryonic lethality whereas post-natal or adult stage deletion of Jak2 results in anemia and thrombocytopenia in mice. However, the role of Jak2 in the maintenance and function of adult HSCs has remained elusive. Understanding the normal function of Jak2 in adult HSC/progenitors is of considerable significance since mutations in Jak2 have been associated with several myeloproliferative neoplasms (MPNs), and most patients treated with Jak2 inhibitors exhibit significant hematopoietic toxicities. To assess the role of Jak2 in adult HSCs, we have utilized a conditional Jak2 knock-out (Jak2 floxed) allele and an inducible MxCre line that can efficiently express Cre recombinase in adult HSC/progenitors after injections with polyinosine-polycytosine (pI-pC). We have found that deletion of Jak2 in adult mice results in pancytopenia, bone marrow aplasia and 100% lethality within 25 to 42 days after pI-pC induction. Analysis of the HSC/progenitor compartments revealed that Jak2-deficiency causes marked decrease in long-term HSCs, short-term HSCs, multipotent progenitors and early progenitors of all hematopoietic lineages, indicating a defect at the earliest stage of adult hematopoietic development. We have found that deletion of Jak2 leads to increased HSC cell cycle entry, suggesting that Jak2-deficiency results in loss of quiescence in HSCs. Jak2-deficiency also resulted in significant apoptosis in HSCs. Furthermore Jak2-deficient bone marrow cells were severely defective in reconstituting hematopoiesis in lethally-irradiated recipient animals. Competitive repopulations experiments also show that Jak2 is essential for HSC functional activity. We also have confirmed that the requirement for Jak2 in HSCs is cell-autonomous. To gain insight into the mechanism by which Jak2 controls HSC maintenance and function, we have performed phospho flow analysis on HSC-enriched LSK (lin-Sca-1+c-kit+) cells. TPO and SCF-evoked Akt and Erk activation was significantly reduced in Jak2-deficient LSK compared with control LSK. Stat5 phosphorylation in response to TPO was also completely inhibited in Jak2-deficient LSK cells. In addition, we observed significantly increased intracellular reactive oxygen species (ROS) levels and enhanced activation of p38 MAPK in Jak2-deficient LSK cells, consistent with the loss of quiescence observed in Jak2-deficient HSCs. Treatment with ROS scavenger N-acetyl cysteine partially rescued the defects in Jak2-deficient HSCs in reconstituting hematopoiesis in lethally irradiated recipient animals. Gene expression analysis revealed significant downregulation of HSC-specific gene sets in Jak2-deficient LSK cells. Taken together, our data strongly suggest that Jak2 plays a critical role in the maintenance of quiescence, survival and self-renewal of adult HSCs. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Minireview: The Stem Cell Next Door: Skeletal and Hematopoietic Stem Cell “Niches” in Bone

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 2957-2962 ◽  
Author(s):  
Paolo Bianco
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
General Concept ◽  
Hematopoietic Stem ◽  
Hsc Niche ◽  
Hematopoietic Stem Cell Niches ◽  
Cellular Components ◽  
Stem Cell Niches

Long known to be home to hematopoietic stem cells (HSC), the bone/bone marrow organ and its cellular components are directly implicated in regulating hematopoiesis and HSC function. Over the past few years, advances on the identity of HSC “niche” cells have brought into focus the role of cells of osteogenic lineage and of marrow microvessels. At the same time, the identity of self-renewing multipotent skeletal progenitors (skeletal stem cells, also known as mesenchymal stem cells) has also been more precisely defined, along with the recognition of their own microvascular niche. The two sets of evidence converge in delineating a picture in which two kinds of stem cells share an identical microanatomical location in the bone/bone marrow organ. This opens a new view on the manner in which the skeleton and hematopoiesis can cross-regulate via interacting stem cells but also a novel view of our general concept of stem cell niches.

Homing and Engraftment of Mobilized Hematopoietic Stem Cells: Involvement of VLA-5.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4943-4943
Author(s):  
Pieter K. Wierenga ◽  
Gerald de Haan ◽  
Bert Dontje ◽  
Ellen Weersing ◽  
Ronald van Os
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Hematopoietic Reconstitution

Abstract VLA-5 has been implicated in the adhesive interactions of stem and progenitor cells with the bone marrow extracellular matrix and stromal cells and is therefore considered to play an important role in the hematopoietic reconstitution after stem cell transplantation. In normal bone marrow (BM) from CBA/H mice 79±3% of the cells in the lineage negative fraction express VLA-5. After mobilization with cyclophosphamide/G-GSF, the number of VLA-5 expressing cells in mobilized peripheral blood cells (MPB) decreases to 38±3%. Despite this low frequency of VLA-5+ cells, however, even when equal numbers of progenitor cells are transplanted MPB cells provide a much faster hematopoietic recovery compared to BM cells. To shed more light on the role of VLA-5 in the process of homing and engraftment, we investigated whether differences in homing potential of the stem cell subsets might be responsible for this enhanced reconstitution. At 3 hours post-transplant, however, no differences in homing efficiency of progenitor and stem cells from MPB and BM grafts in both bone marrow and spleen could be detected. It should be realized that MPB and BM grafts demonstrate different ratios of stem/progenitor cells which might be another explanation for the observed differences in repopulation potential. Furthermore, MPB cells migrating in vitro towards SDF-1α showed potent reconstitution while VLA-5 expression was reduced on these cells. In fact, in vitro treatment with SDF-1α showed further decrease in VLA-5 expressing cells (from 38% to 4%) in the lin- fraction. When equal numbers of MPB were transplanted with and without SDF-1α pretreatment, no difference in hematopoietic reconstitution was observed suggesting a minor role of VLA-5 in homing and engraftment. On the other hand, after VLA-5 blocking an inhibition of 59±7% in the homing of MPB progenitor cells in the bone marrow could be found, whereas homing in the spleen of the the recipients is only inhibited by 11±4%. To elucidate whether the observed enhanced reconstitution could be explained by a selective homing of VLA-5+ cells or a rapid upregulation of VLA-5 expression, cells were labelled with PKH67-GL and transplanted in lethally irradiated recipients. It could be demonstrated that at 3 hours post-transplant cells from MPB grafts showed a rapid increase from 38±3% up to 66±9% of VLA-5+ cells in the bone marrow of the recipient. In the spleen no significant increase in VLA-5+ cells was observed. When MPB cells were transplanted after pretreatment with SDF-1α an increase from 2±1% up to 33±5% of VLA-5+ cells in the bone marrow was detected. When calculating the number of cells recovered from bone marrow, a selective homing of VLA-5+ cells cannot be excluded. Therefore, we also assessed the number of VLA-5+ cells in the PKH+ fraction in peripheral blood from the recipient immediately (½-1 hour) after transplantation but found no increase during that time period. So far it can be concluded that MPB cells show low number of VLA-5+ cells but these cells possess an enhanced hematopoietic reconstitution potential. Homing of progenitor cells to the spleen seems to be less dependent on VLA-5 expression than homing to the bone marrow. A rapid upregulation of VLA-5 expression on engrafting MPB cells early after transplantation does not occur and hence our data are suggestive for the preferential homing of VLA-5+ cells in the bone marrow after transplantation.

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