Mitochondrial Morphology Controls Hematopoietic Stem Cell (HSC) Self-Renewal and Confers HSC Divisional Memory

Adult hematopoietic stem cell (HSC) have extensive regenerative capacity; but recent evidence strongly indicate that their actual capacity for self-renewal is limited. HSC attrition occurs with cumulative divisions and after acute stress, causing reduction in regenerative capacity of the progeny. The principal mechanism driving the loss of HSC potency with stress hematopoiesis is not completely understood. We will show and discuss the concept that regulatory programs that are activated with HSC activation and cell cycle entry cause a permanent remodeling of mitochondria. Mitochondria do not return to homeostasis after replicative stress despite HSC re-entry into quiescence and termination of the metabolic programs that were activated with HSC cell cycle entry. HSC keep dysfunctional mitochondria after replicative stress and this loss in mitochondrial fidelity drives the decline of the HSC pool after regenerative stress. The mitochondrial remodeling with replicative stress is at least in part due to a loss in mitochondrial quality control, notably Drp1-mediated mitochondrial dynamics. Further, single cell RNA-seq data indicate that HSC carrying dysfunctional mitochondria fail to synchronize the transcriptional control of core cell cycle and metabolic components in subsequent division providing unexpected mechanism of why HSC that have divided are less potent than HSC that have never divided in similar microenvironment. Thus, the loss of fidelity of mitochondria homeostasis drives HSC attrition and serves as one source of cellular memory of hematopoietic stem cell replicative history.