1 - Joint Session
Oral presentations Experimental hematology / oncology
Nov. 22, 2023, 8:30 a.m. - 10:00 a.m., Boston 1-2
Hematopoietic stem cell (HSC) aging drives systemic aging
M. A. Sarangdhar1, N. Andina1, A. Tardivel1, M. Hallal1, G. Bombaci1, V. Chennupati2, Y. Banz1, I. Keller1, S. Brot1, A. Angelillo-Scherrer1, R. Allam1, Presenter: M. A. Sarangdhar1 (1Bern, 2Lausanne)
Aging entails the gradual decline of tissue and stem cell function, potentially impacting homeostasis and contributing to aging. Although the hypothalamus and its stem cells are known to affect systemic aging, it's unclear if other stem cells, especially HSCs, also contribute. In mammals, HSCs maintain blood production but exhibit age-related changes, increased myeloid output and decreased erythroid/lymphoid output, posing a risk for age-related malignancies. This study explores the potential contribution of aging HSCs to organismal aging.
We created hematopoietic-specific Ribonuclease inhibitor (Rnh1)-deleted mice via cross of conditional knockout (Rnh1fl/fl) with Vav1-iCre mice and an inducible mouse model (Rnh1fl/fl Mx1-Cre+) by crossing Rnh1fl/fl mice with Mx1-Cre strain. We analysed these mice using various methods, including peripheral blood assessment, bone marrow transplantation, competitive transplantation assays, histopathology, RNA-sequencing of FACS sorted HSCs and GMPs, GSEA for aged HSC signatures, cell-cycle analysis, p-CHK1 staining, Co-IP, mass-spec experiments. Further, Molecular docking and confocal microscopy were used to confirm RNH1 colocalizing with identified partner Cyclin-dependent kinase 1 (CDK1). To assess the impact of CDK1 inhibition on HSC aging phenotype polyI:C treated Rnh1fl/fl Mx1-Cre+(Rnh1-/-) BM transplanted mice administered with CDK1 inhibitor RO-3306.
RNH1 gene deletion in adult mouse HSCs caused premature and chronic HSC aging with aberrant HSC expansion, myeloid bias, reduced lymphopoiesis (Fig.1a, b), and diminished repopulating ability. This accelerated HSC aging resulted in premature organismal aging with reduced healthy lifespan, organ hypoplasia, kyphosis, and decreased subcutaneous fat (Fig.1c-h). Global gene expression analysis of HSCs revealed upregulation of cell-cycle and proliferation related genes in Rnh1-/- cells along with significant enrichment of the aged HSC signature in Rnh1-/- HSCs in GSEA (Fig.1i). Mechanistically, RNH1 loss drove cell cycle dysregulation by enhancing CDK1 function, contributing to HSC aging (Fig.1j-p).
Our study highlights vital role of RNH1 in HSC aging and reveal significance of HSCs in mediating systemic aging. We show aged HSCs drive organismal aging and suggest targeting HSC aging as a valuable therapeutic strategy for hematological malignancies and overall healthy aging.