Abstract
Regulation of stem cell fate is best understood at the level of gene and protein regulatory networks, though it is now clear that multiple cellular organelles also have critical impacts. A growing appreciation for the functional interconnectedness of organelles suggests that an orchestration of integrated biological networks functions to drive stem cell fate decisions and regulate metabolism. Metabolic signaling itself has emerged as an integral regulator of cell fate including the determination of identity, activation state, survival, and differentiation potential of many developmental, adult, disease, and cancer-associated stem cell populations and their progeny. As the primary adenosine triphosphate-generating organelles, mitochondria are well-known regulators of stem cell fate decisions, yet it is now becoming apparent that additional organelles such as the lysosome are important players in mediating these dynamic decisions. In this review, we will focus on the emerging role of organelles, in particular lysosomes, in the reprogramming of both metabolic networks and stem cell fate decisions, especially those that impact the determination of cell identity. We will discuss the inter-organelle interactions, cell signaling pathways, and transcriptional regulatory mechanisms with which lysosomes engage and how these activities impact metabolic signaling. We will further review recent data that position lysosomes as critical regulators of cell identity determination programs and discuss the known or putative biological mechanisms. Finally, we will briefly highlight the potential impact of elucidating mechanisms by which lysosomes regulate stem cell identity on our understanding of disease pathogenesis, as well as the development of refined regenerative medicine, biomarker, and therapeutic strategies.
Highlights
Regulation of stem cell fate is best understood at the level of gene and protein regulatory networks, though it is clear that multiple cellular organelles have critical impacts
Oxidative phosphorylation is linked to the mitochondrial electron transport chain (ETC) and fueled by energy precursors generated through the tricarboxylic acid cycle (TCA)
We found that increased lysosome biogenesis preceded later changes in mitochondrial content, which correlated with aberrant activation of oxidative metabolism uniquely in TSC2−/− neural stem cell (NSC) (Delaney et al, 2019)
Summary
Stem cell fate decisions, including the determination of cellular identity, are intimately linked to gene expression networks with each decision driven by wide-spread transcriptional changes (Walker et al, 2007; Julian et al, 2013, 2017b; Julian and Blais, 2015; Pinto et al, 2018; Abdolhosseini et al, 2019; Wells and Choi, 2019). The successful development, long-term homeostasis, and post-injury repair of organs and tissues is dependent on the pliability in cell fate decisions that these integrated biological networks permit. This flexibility can give rise to the aberrant stem cell populations that underlie pathology in many diseases including tumor syndromes. This double-edged sword of cell fate pliancy is paralleled by dynamics in metabolic signaling pathways. It is crucial to understand the breadth of regulatory processes and factors that contribute to the biological networks underlying metabolic control and to elucidate their impacts on cell fate
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