Hematopoietic stem cells (HSCs) reside in the bone marrow (BM), are quiescent, can self renew, and generate all lineages of the hematopoietic system. Despite significant progress in our understanding of mechanisms involved in self-renewal, differentiation and quiescence, a coherent picture of how these mechanisms act in concert to regulate steady-state function and homeostatic responses of HSCs in vivo has not emerged yet. Furthermore, reliable renewal of HSCs in vitro has not been achieved, while there is overwhelming evidence that HSC self-renewal occurs in vivo. This implies that despite the identification of dozens of cytokines and of more than 200 genes that affect HSC function in knockout studies, and despite the publication of multiple studies on genome-wide expression and epigenetic signatures, significant gaps in our understanding remain. A particular gap is our understanding of the organellar cell biology of HSCs. HSCs rely predominantly on glycolytic ATP production, while many mature cells use mitochondrial oxidative phosphorylation (OXPHOS). Preferential use of glycolysis in stem cells suggests that mitochondrial respiration is more dispensable for HSCs than for progenitors, a notion supported by experimental data. These findings raise the question whether mitochondria play a role in HSCs that is not directly related to ATP production. In addition to ATP production, mitochondria are also required for several biosynthetic pathways and intermediary metabolism, apoptosis and intracellular calcium homeostasis. We show in our preliminary data that mitochondria are regulated in an exceptional fashion in HSCs, and that interfering with this regulation affects HSC function, at least in part by buffering intracellular calcium (Cai2+), which we found to be strikingly low in HSCs compared to progenitors and non-hematopoietic cells. The goal of is the proposal is to better define regulation of mitochondria in HSC, its impact on Cai2+, and HSC on maintenance, identity and function.
Hematopoietic stem cells generate all cells of the blood and immune system, and are critical for the development of leukemia and its treatment by bone marrow transplantation. The mechanisms underlying the function of these cells are not well understood however. In this proposal, we examine the role of mitochondria, which fulfill diverse roles in cell biology but whose role in the biology of hematopoietic stem cells has never been analyzed in depth.
| Corrigan, David J; Luchsinger, Larry L; Justino de Almeida, Mariana et al. (2018) PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature. J Clin Invest 128:3250-3264 |
| Chen, Xiaowei; Deng, Huan; Churchill, Michael J et al. (2017) Bone Marrow Myeloid Cells Regulate Myeloid-Biased Hematopoietic Stem Cells via a Histamine-Dependent Feedback Loop. Cell Stem Cell 21:747-760.e7 |
| de Almeida, Mariana Justino; Luchsinger, Larry L; Corrigan, David J et al. (2017) Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells. Cell Stem Cell 21:725-729.e4 |
| Snoeck, Hans-Willem (2017) Mitochondrial regulation of hematopoietic stem cells. Curr Opin Cell Biol 49:91-98 |
