Abstract: Hematopoietic stem cells (HSCs) are capable of both self-renewal and multi-lineage differentiation, which govern the lifelong maintenance of hematopoietic homeostasis. Although HSCs have the potential to expand functional stem cells by self-renewal, their divisions often induce their differentiation in several cases. Thus, it remains unclear how HSCs determine cell fate during or after divisions. To address this question, we firstly focused on the role of Glu catabolism in HSCs, since self-renewing mouse HSCs during hematopoietic regeneration showed greatly lower intracellular Glu level compared to HSCs attenuating stem cell features during ex vivo culture. Typically, HSCs elevated intracellular Glu level via JAK-STAT signaling to promote their proliferation through aminotransferase reactions, which is Glu catabolic pathway. In this context, we identified glutamate dehydrogenase (GLUD1), an enzyme responsible for another Glu catabolic pathway, as one of the key factors to induce HSC differentiation. Strikingly, GLUD1 inhibition more efficiently maintained stem cell features without impairing their divisional activity, facilitating functional HSC expansion through self-renewing divisions. Crucially, this beneficial effect required robust JAK2-STAT5 signaling. Mechanistically, GLUD1 interacted with STAT5a, an association that was disrupted, when the inhibition of GLUD1-mediated Glu catabolism preserved HSC features. Moreover, when HSC divisions were robustly driven despite low intracellular Glu level in vitro by mimicking BM environments during hematopoietic regeneration, functional HSCs were expanded similarly to those under GLUD1 inhibition. Our findings propose that, particularly after HSC divisions under robust JAK-STAT signaling, GLUD1 acts as a fate determinant in newly generated cells by modulating its interaction with STAT family in response to intracellular Glu levels. Overall, our findings proposed that GLUD1 determines HSC fate after divisions under robust JAK-STAT signaling, highlighting the important link between Glu catabolism and cytokine signaling in HSC fate decisions.
Funding Source: This study is supported with an unrestricted grant from the Chemo-Sero-Therapeutic Research Institute (KAKETUSKEN).
