Autophagy is a signature of a signaling network that maintains hematopoietic stem cells

Abstract

Hematopoietic stem cells (HSCs) are able to self-renew and to differentiate into all blood cells. HSCs reside in a low-perfusion niche and depend on local signals to survive and to maintain the capacity for self-renewal. HSCs removed from the niche are unable to survive without addition of hematopoietic cytokines and rapidly lose their ability to self-renew. We reported previously that inhibition of both GSK-3 and mTORC1 is essential to maintain long-term HSCs ex vivo. Although Wnt/β-catenin signaling downstream of GSK-3 is required for this response, the downstream effectors of mTORC1 remain undefined. We now report that HSCs express a pro-autophagic gene signature and accumulate LC3 puncta only when both mTORC1 and GSK-3 are inhibited, identifying autophagy as a signature for a signaling network that maintains HSCs ex vivo. In addition, these conditions sustain HSC repopulating function despite an increased rate of global translation. Together, these findings provide new insight into the relative contributions of various mTORC1 outputs toward the maintenance of HSC function and build upon the growing body of literature implicating autophagy and tightly controlled protein synthesis as important modulators of diverse stem cell populations.

Multifaceted Roles of GSK‐3 in Cancer and Autophagy‐Related Diseases

“…It has also been clarified that GSK-3, in the absence of growth factors, is able to activate the acetyltransferase KAT5/TIP60, which in turn stimulates the protein kinase ULK1 to induce autophagy [ 72 ]. Remarkably, GSK-3 seems to play a key role also in stemness; in fact, inhibition of both GSK-3 and mTORC1 induces a proautophagic gene signature in hematopoietic stem cells, which is crucial to maintain their self-renewal ability [ 73 ].…”

Differences of basic and induced autophagic activity between K562 and K562/ADM cells

“…Over the past few decades, basal autophagy was reported to remove misfolded proteins and damaged organelles to maintain cellular quality and health, involved in many physical processes of cells such as cellular turnover, differentiation and development (9)(10)(11). Abnormal basal autophagy can lead to various human diseases including cancer, neurodegenerative disorders, autoimmunity disease and inflammation (12)(13)(14)(15).…”

Ex vivo HSC expansion challenges the paradigm of unidirectional human hematopoiesis

“…Autophagy activation limits the number of active mitochondria, mitigates the deleterious effects of cellular stress, and thus enables the retention of HSC primitive metabolic state. [50][51][52][53] Quiescent, self-renewing, and differentiating HSCs have distinct metabolic profiles. Low mitochondrial activity offers protective advantages for resting long-term HSCs due to the generation of low levels of ROS.…”