Abstract A10: Taz regulates aging of hematopoietic stem cells

During aging, several tissues display a progressive functional decline potentially leading to malfunction of whole organ systems. This phenomenon can also be observed in the hematopoietic system since aged hematopoietic stem cells (HSCs) display several cell-intrinsic defects, e.g., a strongly reduced self-renewal capacity as well as a skewing towards myeloid differentiation. To investigate a potential involvement of the Hippo pathway in the aging of HSCs, we performed RNA-sequencing in several stem and progenitor populations of young and aged mice, respectively. Here, we identified Taz as one of the most strongly upregulated genes, specifically in long-term hemtatopoietic stem cells (LT-HSCs), those cells that are at the apex of the hematopoietic system. Further analyses revealed that Taz actively contributes to the aging-specific gene expression changes in LT-HSCs and that Tazhigh cells accumulate over time in the LT-HSC compartment. Furthermore, we identified a novel surface marker as a Taz target gene, which allows us to trace Taz activity in the aging mouse and separate Tazhigh from Tazlow cells. Strikingly, our functional characterization revealed that Tazlow cells closely resemble young LT-HSCs whereas Tazhigh cells display a gene expression program that is found in aged LT-HSCs. Consistent with these observations, Tazhigh cells are functionally impaired, e.g., during cell cycle re-entry. Our observations demonstrate that Taz is potently induced during aging of the blood system and most prominently in the LT-HSC compartment where it contributes to age-dependent gene expression changes and functional decline of hematopoietic stem cells. Citation Format: Anna Mura-Meszaros, Florian Heidel, Bjoern von Eyss. Taz regulates aging of hematopoietic stem cells [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A10.