Stromal STAT5-Mediated Trophic Activity Regulates Hematopoietic Niche Factors.

Autor:	Wang Z; Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA.; Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA., Emmel G; Department of Biomedical Engineering, School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA., Lim HS; Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA., Zhu W; Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA.; Center for Inflammation, Immunity & Infection, Georgia State University Institute for Biomedical Sciences, Atlanta, GA, USA., Kosters A; Department of Medicine, Lowance Center for Human Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA., Ghosn EEB; Department of Medicine, Lowance Center for Human Immunology and Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA., Qiu P; Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA., Bunting KD; Department of Pediatrics, Division of Hem/Onc/BMT, Emory University, Atlanta, GA, USA.; Department of Pediatrics, Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA, USA.
Jazyk:	angličtina
Zdroj:	Stem cells (Dayton, Ohio) [Stem Cells] 2023 Oct 08; Vol. 41 (10), pp. 944-957.
DOI:	10.1093/stmcls/sxad055
Abstrakt:	Signal transducer and activator of transcription 5 (STAT5a and STAT5b) are intrinsically critical for normal hematopoiesis but are also expressed in stromal cells. Here, STAT5ab knockout (KO) was generated with a variety of bone marrow hematopoietic and stromal Cre transgenic mouse strains. Vav1-Cre/+STAT5abfl/fl, the positive control for loss of multipotent hematopoietic function, surprisingly dysregulated niche factor mRNA expression, and deleted STAT5ab in CD45neg cells. Single-cell transcriptome analysis of bone marrow from Vav1-Cre/+ wild-type or Vav1-Cre/+STAT5abfl/fl mice showed hematopoietic stem cell (HSC) myeloid commitment priming. Nes+ cells were detected in both CD45neg and CD45+ clusters and deletion of STAT5ab with Nes-Cre caused hematopoietic repopulating defects. To follow up on these promiscuous Cre promoter deletions in CD45neg and CD45+ bone marrow cell populations, more stroma-specific Cre strains were generated and demonstrated a reduction in multipotent hematopoietic progenitors. Functional support for niche-supporting activity was assessed using STAT5-deficient mesenchymal stem cells (MSCs). With Lepr-Cre/+STAT5abfl/fl, niche factor mRNAs were downregulated with validation of reduced IGF-1 and CXCL12 proteins. Furthermore, advanced computational analyses revealed a key role for STAT5ab/Cish balance with Cish strongly co-expressed in MSCs and HSCs primed for differentiation. Therefore, STAT5ab-associated gene regulation supports the bone marrow microenvironment. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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