Longâterm engraftment of primary bone marrow stroma promotes hematopoietic reconstitution after transplantation
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Jean-Paul Abbuehl
PROVIDER: E-GEOD-79091 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Human bone marrow stromal cells (BMSCs) are key elements of the hematopoietic environment and they play a central role in bone and bone marrow physiology. However, how key BMSC functions are regulated is largely unknown. We analyzed the role of the immediate early response transcription factor EGR1 as key BMSC regulator and found that EGR1 was highly expressed in prospectively-isolated primary BMSCs, downregulated upon culture, and lower in non-CFU-F-containing CD45neg BM cells. Furthermore, EGR1 expression was lower in proliferative regenerating adult and fetal primary cells compared to adult steady-state BMSCs. Accordingly, EGR1 overexpression markedly decreased BMSC proliferation but considerably improved hematopoietic stroma support function as indicated by an increased production of transplantable CD34+CD90+ hematopoietic stem cells in expansion co-cultures. The improvement of BMSC stroma support function was mediated by increased expression of hematopoietic supporting genes, such as VCAM1 and CCL28. On the other hand, EGR1 knockdown increased ROS-mediated BMSC proliferation, and clearly reduced BMSC hematopoietic stroma support potential. These findings thus show that EGR1 is a key BMSC transcription factor with a dual role in regulating proliferation and hematopoietic stroma support function that is controlling a genetic program to coordinate the specific functions of BMSC in their different biological contexts.
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Project description:The bone marrow (BM) niche regulates multiple HSC processes. Clinical treatment for hematological malignancies, by HSC transplantation often requires preconditioning total body irradiation, which severely and irreversibly impairs the BM niche and HSC regeneration. Novel strategies to enhance HSC regeneration in irradiated BM are needed. We compared the effects of niche factors EGF, FGF2 and PDGFB on HSC hematopoietic regeneration using human MSCs that were transduced with these factors via lentiviral vectors. Among above niche factors tested, PDGFB-MSCs most significantly improved human hematopoietic cell engraftment in immunodeficient mice. PDGFB-MSC-treated BM more efficiently enhanced transplanted human HSC self-renewal in secondary transplantations from primary recipients. Although PDGFB-MSCs did not directly increase HSC expansion in vitro, GSEA revealed anti-apoptotic signaling being increased in PDGFB-MSCs versus GFP-MSCs. PDGFB-MSCs had enhanced survival and expansion after transplantation, leading to an enlarged humanized niche cell pool. Our study demonstrates the efficacy of MSC-mediated niche factors in clinical HSC transplantation for patients.
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Project description:Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial cells by constantly probing their surroundings with dynamic extensions. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies.
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Project description:Microglia are yolk sac-derived macrophages residing in the parenchyma of brain and spinal cord, where they interact with neurons and other glial cells by constantly probing their surroundings with dynamic extensions. After different conditioning paradigms and bone marrow (BM) or hematopoietic stem cell (HSC) transplantation, graft-derived cells seed the brain and persistently contribute to the parenchymal brain macrophage compartment. Here we establish that graft-derived macrophages acquire, over time, microglia characteristics, including ramified morphology, longevity, radio-resistance and clonal expansion. However, even after prolonged CNS residence, transcriptomes and chromatin accessibility landscapes of engrafted, BM-derived macrophages remain distinct from yolk sac-derived host microglia. Furthermore, engrafted BM-derived cells display discrete responses to peripheral endotoxin challenge, as compared to host microglia. In human HSC transplant recipients, engrafted cells also remain distinct from host microglia, extending our finding to clinical settings. Collectively, our data emphasize the molecular and functional heterogeneity of parenchymal brain macrophages and highlight potential clinical implications for HSC gene therapies aimed to ameliorate lysosomal storage disorders, microgliopathies or general monogenic immuno-deficiencies.
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Project description:The identity of cells that establish the hematopoietic microenvironment (HME) in human bone marrow (BM), and of skeletal ("mesenchymal") stem cells (SSCs) found in BM stroma, have long remained elusive. We show that MCAM/CD146-expressing, subendothelial cells in human BM stroma are both the self-renewing SSCs and the cells that transfer the HME at heterotopic sites upon transplantation. Establishment and self-renewal of SSCs in developing BM in vivo occurs via specific, dynamic interactions with developing sinusoids. Non-differentiated SSCs residing on the sinusoidal wall, but not differentiated osteoblasts, express Angiopoietin-1 (a pivotal molecule of the HSC "niche" involved in vascular remodeling). Our data reveal the functional relationships between establishment of the HME in vivo, establishment of SSCs in BM sinusoids, and angiogenesis. Keywords: comparative genomics, genetic modification
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Project description:Hematopoietic stem cells (HSCs) inhabit distinct microenvironments within the adult bone marrow (BM) that govern the delicate balance between HSC quiescence, self-renewal, and differentiation. It has been suggested that quiescent HSCs localize adjacent to BM arteriole endothelial cells in a significant and non-random distribution. This data suggests that the arteriole BM vascular niche may be the primary HSC niche. Because the BM arteriole niche is composed of tightly-associated pericytes, including smooth muscle actin+, LepR+, Nestin+, NG2+, and nonmyelinating Schwann cells, we sought to begin to uncouple the arteriole BM EC niche by examining its capacity to support the maintenance and expansion of HSCs ex vivo and in vivo. We developed a method to isolate and culture BM arteriole endothelial cells in serum-/growth factor-free conditions, allowing for a non-biased approach to examining their instructive function. Utilizing our protocol, we demonstrate that BM endothelial cells, but not BM stromal cells, have the capacity to expand long-term repopulating, multi-lineage HSCs in lieu of complex serum and cytokine supplementation. In addition, transplantation of arteriole endothelial cells promoted rapid hematopoietic recovery and protected HSCs following an LD50 dose of myeloablative irradiation. These data demonstrate that arteriole-derived BM endothelial cells are endowed with the necessary signals to support the self-renewal and regenerative capacity of LT-HSCs and that transplantation of arteriole BM endothelial cells could be used as a therapeutic means to decrease pancytopenias associated with myeloablative treatments to treat a wide array of disease states. Transcriptome sequencing of bone marrow endothelial cells and bone marrow stroma, in vitro and in vivo, with and without HSC co-culture.
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Project description:Acute Myeloid Leukemia (AML) is characterized by the clonal expansion of immature myeloblasts originating from leukemic stem cells (LSCs) niched within the bone marrow. Bone marrow stromal cells (BMSC) and tumor-stroma interactions play a prominent role in the evolution of this disease. BMSC-mediated protection of leukemic cells involves several mechanisms, including interactions between adhesion molecules, the secretion of cytokines/chemokines and the release of extracellular vesicles produced by the surrounding non-haemopoietic BM cells. Recent studies even suggest that autophagy in the tumor stroma is associated with leukemia progression, survival and resistance. Thus, it seems widely evident that the microenvironment profile affects the prognosis and influences the efficacy of anti-cancer therapies. Yet, although widely explored, the crosstalk between leukemic and stromal cells remains poorly understood. Syntenin (directing endocytosed SDC and receptor cargo back to cell surfaces and/or to endosomal intraluminal vesicles and exosomes) is known to coordinate inter-cellular communications. Using syntenin-knockout mice, we aimed to clarify the role of environmental-syntenin in the progression of AML, a disease in which the role of (tumor/host) syntenin was not yet investigated. To address the role of host-syntenin in AML, I extensively used the mouse FLB1 AML-like model (generous gift of O. Herault, Tours). Strikingly, FLB1 cells show a marked gain in aggressiveness when serially transplanted a syntenin-KO host. This aggressive behavior is cell-autonomous, as not reversed by back transplantation into WT hosts. Moreover, ‘aggressive’ FLB1 blasts, raised by education in a syntenin-negative in vivo background, are able to survive and grow in vitro in the absence of stroma, suggesting the cell-autonomous activation of survival pathways. Surprisingly, this gain of aggressiveness is not accompanied by a noticeable morphotypic or transcriptomic signature. However using quantitative proteomics we highlighted altered mRNA translational control. Aggressive FLB1 show a significant up-regulation of several factors, but most marked for EEF1A2, previously shown to have pro-oncogenic activities in various cancers..Globally, these findings are also consistent with the emerging notion that altered mRNA translational control is a critical factor in cancer development and progression.
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Project description:Leukemia stem cells (LSC) are not eradicated in chronic myeloid leukemia (CML) patients responding to tyrosine kinase inhibitor treatment. Bone marrow (BM) mesenchymal niches play an essential role in hematopoietic stem cell (HSC) maintenance. Here, we examined leukemia-induced alterations in mesenchymal progenitor populations using a murine CML model. 6C3+ stroma-forming progenitors were increased in CML BM, and demonstrated enhanced LSC but reduced HSC support compared to their normal counterparts. CML 6C3 cells showed enhanced TNFa-related gene signatures, and upregulated CXCL1 expression. TNFα signaling contributed to expansion and increased CXCL1 expression by 6C3 cells in CML BM. The CXCL1 receptor CXCR2 was upregulated in in LSC, and CXCR2 inhibition significantly reduced LSC growth both in vitro and in vivo. In conclusion, TNFα-induced alterations in stromal progenitors in CML BM result in enhanced CML LSC growth via CXCL1-CXCR2 signaling. Targeting this axis represents a novel therapeutic strategy to inhibit BM niche-protected LSC.
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