Glia maturation factor-γ is required for initiation and maintenance of hematopoietic stem and progenitor cells.

Autor: Li H; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China., Luo Q; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China., Cai S; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China., Tie R; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China., Meng Y; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China., Shan W; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China., Xu Y; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China., Zeng X; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China., Qian P; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China. axu@zju.edu.cn.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China. axu@zju.edu.cn.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China. axu@zju.edu.cn.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China. axu@zju.edu.cn.; Center of Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, 310012, People's Republic of China. axu@zju.edu.cn.; Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, 310012, Zhejiang, People's Republic of China. axu@zju.edu.cn.; School of Medicine, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, People's Republic of China. axu@zju.edu.cn., Huang H; Bone Marrow Transplantation Center, School of Medicine, The First Affiliated Hospital, Zhejiang University, No. 79 Qingchun Road, Hangzhou, 310012, Zhejiang, People's Republic of China. huanghe@zju.edu.cn.; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, Hangzhou, 311121, People's Republic of China. huanghe@zju.edu.cn.; Institute of Hematology, Zhejiang University, Hangzhou, People's Republic of China. huanghe@zju.edu.cn.; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, People's Republic of China. huanghe@zju.edu.cn.; Center of Stem Cell and Regenerative Medicine, School of Medicine, Zhejiang University, Hangzhou, 310012, People's Republic of China. huanghe@zju.edu.cn.
Jazyk: angličtina
Zdroj: Stem cell research & therapy [Stem Cell Res Ther] 2023 Apr 30; Vol. 14 (1), pp. 117. Date of Electronic Publication: 2023 Apr 30.
DOI: 10.1186/s13287-023-03328-1
Abstrakt: Background: In vertebrates, hematopoietic stem and progenitor cells (HSPCs) emerge from hemogenic endothelium in the floor of the dorsal aorta and subsequently migrate to secondary niches where they expand and differentiate into committed lineages. Glia maturation factor γ (gmfg) is a key regulator of actin dynamics that was shown to be highly expressed in hematopoietic tissue. Our goal is to investigate the role and mechanism of gmfg in embryonic HSPC development.
Methods: In-depth bioinformatics analysis of our published RNA-seq data identified gmfg as a cogent candidate gene implicated in HSPC development. Loss and gain-of-function strategies were applied to study the biological function of gmfg. Whole-mount in situ hybridization, confocal microscopy, flow cytometry, and western blotting were used to evaluate changes in the number of various hematopoietic cells and expression levels of cell proliferation, cell apoptosis and hematopoietic-related markers. RNA-seq was performed to screen signaling pathways responsible for gmfg deficiency-induced defects in HSPC initiation. The effect of gmfg on YAP sublocalization was assessed in vitro by utilizing HUVEC cell line.
Results: We took advantage of zebrafish embryos to illustrate that loss of gmfg impaired HSPC initiation and maintenance. In gmfg-deficient embryos, the number of hemogenic endothelium and HSPCs was significantly reduced, with the accompanying decreased number of erythrocytes, myelocytes and lymphocytes. We found that blood flow modulates gmfg expression and gmfg overexpression could partially rescue the reduction of HSPCs in the absence of blood flow. Assays in zebrafish and HUVEC showed that gmfg deficiency suppressed the activity of YAP, a well-established blood flow mediator, by preventing its shuttling from cytoplasm to nucleus. During HSPC initiation, loss of gmfg resulted in Notch inactivation and the induction of Notch intracellular domain could partially restore the HSPC loss in gmfg-deficient embryos.
Conclusions: We conclude that gmfg mediates blood flow-induced HSPC maintenance via regulation of YAP, and contributes to HSPC initiation through the modulation of Notch signaling. Our findings reveal a brand-new aspect of gmfg function and highlight a novel mechanism for embryonic HSPC development.
(© 2023. The Author(s).)
Databáze: MEDLINE
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