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Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF.

ABSTRACT: Endothelial cells and leptin receptor+ (LepR+) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including stem cell factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER+ progenitors, which represent ?5% of LepR+ cells, and proliferate after irradiation. Scf deletion using Adipoq-Cre/ER inhibited haematopoietic regeneration after irradiation or 5-fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR+ cells, but not endothelial, haematopoietic or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq-Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 'fatless' mice exhibited delayed haematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes haematopoietic regeneration.

SUBMITTER: Zhou BO

PROVIDER: S-EPMC5536858 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF.

Zhou Bo O BO Yu Hua H Yue Rui R Zhao Zhiyu Z Rios Jonathan J JJ Naveiras Olaia O Morrison Sean J SJ

Nature cell biology 20170717 8

Endothelial cells and leptin receptor+ (LepR+) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including stem cell factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER+ progenitors, which represent ∼5% of LepR+ cells, and proliferate after irradiation. Scf dele ...[more]

PMID: 28714970

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Project description:Background: Thin endometrial tissue is a leading cause of embryo transfer failure, potentially contributing to sustained infertility and associated adverse outcomes. The application of exosomes derived from autologous or allogeneic bone marrow-derived stem cells (BMSCs) has been used to promote uterine repair following injury, and there is also prior evidence that stem cell transplantation can bolster fertility. Genetic modifications represent a primary approach to enhancing exosomal therapy strategies. The present study thus explored the effects of Cardiotrophin-1 (CTF1)-modified BMSCs-exo on fertility-related outcomes. Methods: An adenoviral vector was used to generate CTF1-overexpressing BMSCs (C-BMSCs), after which exosomes were isolated from control BMSCs (BMSC-exos) and C-BMSCs (C-BMSC-exos). The angiogenic effects of C-BMSC-exo treatment were assessed through analyses of endothelial cell proliferation and tube formation. Model rats exhibiting endometrial thinning were administered C-BMSCs-exo, after which the effects of such treatment were assessed through H&E staining, Masson's trichrome staining, and immunofluorescence analyses. The mechanistic basis for the proangiogenic effects of CTF1 as a driver of endometrial regeneration was additionally explored. Results: C-BMSC-exo treatment of HUVECs was associated with enhanced neovascularization, as evidenced by improved in vitro proliferation, migration, and tube formation. Importantly, such treatment was also linked to tissue regeneration, neovascularization, and the suppression of localized tissue fibrosis in vivo. Regenerated endometrial tissue exhibited higher embryo receptivity and was associated with higher birth rates in treated rats. The upregulation of the JAK/PI3K/mTOR/STAT3 signaling pathways in C-BMSC-exo-treated rats may underscore the mechanistic basis whereby CTF1 can positively impact endometrial angiogenesis and regeneration. Conclusion: Our data suggest that exosomes produced by CTF1-modified BMSCs can more effectively promote the regeneration of endometrial and myometrial tissues, driving neovascularization in a manner that improves endometrial receptivity in a rat model system, highlighting the therapeutic promise of this approach for patients diagnosed with endometrial thinning.

Project description:BackgroundMesenchymal stem cells (MSCs) are known to have different differentiation potential depending on the tissue of origin. Dedifferentiated fat cells (DFATs) are MSC-like multipotent cells that can be prepared from mature adipocytes by ceiling culture method. It is still unknown whether DFATs derived from adipocytes in different tissue showed different phenotype and functional properties. In the present study, we prepared bone marrow (BM)-derived DFATs (BM-DFATs), BM-MSCs, subcutaneous (SC) adipose tissue-derived DFATs (SC-DFATs), and adipose tissue-derived stem cells (ASCs) from donor-matched tissue samples. Then, we compared their phenotypes and multilineage differentiation potential in vitro. We also evaluated in vivo bone regeneration ability of these cells using a mouse femoral fracture model.MethodsBM-DFATs, SC-DFATs, BM-MSCs, and ASCs were prepared from tissue samples of knee osteoarthritis patients who received total knee arthroplasty. Cell surface antigens, gene expression profile, and in vitro differentiation capacity of these cells were determined. In vivo bone regenerative ability of these cells was evaluated by micro-computed tomography imaging at 28 days after local injection of the cells with peptide hydrogel (PHG) in the femoral fracture model in severe combined immunodeficiency mice.ResultsBM-DFATs were successfully generated at similar efficiency as SC-DFATs. Cell surface antigen and gene expression profiles of BM-DFATs were similar to those of BM-MSCs, whereas these profiles of SC-DFATs were similar to those of ASCs. In vitro differentiation analysis revealed that BM-DFATs and BM-MSCs had higher differentiation tendency toward osteoblasts and lower differentiation tendency toward adipocytes compared to SC-DFATs and ASCs. Transplantation of BM-DFATs and BM-MSCs with PHG enhanced bone mineral density at the injection sites compared to PHG alone in the mouse femoral fracture model.ConclusionsWe showed that phenotypic characteristics of BM-DFATs were similar to those of BM-MSCs. BM-DFATs exhibited higher osteogenic differentiation potential and bone regenerative ability compared to SC-DFATs and ASCs. These results suggest that BM-DFATs may be suitable sources of cell-based therapies for patients with nonunion bone fracture.

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Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF.

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Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF.

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