Julian Lisa M, Stanford William L
Department of Biological Sciences, Simon Fraser University, Burnaby, BC, Canada.
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Front Cell Dev Biol. 2020 Jul 7;8:591. doi: 10.3389/fcell.2020.00591. eCollection 2020.
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.
尽管现在已经清楚多个细胞器也具有关键影响，但干细胞命运的调控在基因和蛋白质调控网络层面上最为人所理解。对细胞器功能相互联系的认识不断加深，这表明整合生物网络的协同作用有助于驱动干细胞命运决定并调节新陈代谢。代谢信号本身已成为细胞命运的一个不可或缺的调节因子，包括许多发育、成体、疾病和癌症相关干细胞群体及其后代的身份确定、激活状态、存活和分化潜能。作为产生三磷酸腺苷的主要细胞器，线粒体是干细胞命运决定的著名调节因子，但现在越来越明显的是，诸如溶酶体等其他细胞器在介导这些动态决定中也起着重要作用。在本综述中，我们将重点关注细胞器，特别是溶酶体，在代谢网络重编程和干细胞命运决定中的新作用，尤其是那些影响细胞身份确定的作用。我们将讨论溶酶体参与的细胞器间相互作用、细胞信号通路和转录调控机制，以及这些活动如何影响代谢信号。我们将进一步回顾最近的数据，这些数据将溶酶体定位为细胞身份确定程序的关键调节因子，并讨论已知或假定的生物学机制。最后，我们将简要强调阐明溶酶体调节干细胞身份的机制对我们理解疾病发病机制以及对精准再生医学、生物标志物和治疗策略发展的潜在影响。
