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Developmental Biology - Human MicroBiome Autophagy
How 'Self-Eating' Is Regulated In Stem Cells
The 'Self-eating' process of stem cells may regulate cell repair, differentiation and may lead to regeneration therapies...
Self-eating or chaperone-mediated autophagy (CMA) in embryonic stem cells may become a promising new therapy target for repair and regeneration of damaged cells and related organs.
Autophagy is a cell-eating mechanism needed for survival and function in most living organisms. When cells self-eat, the detritis is delivered to that cell's lysosomes, organelles that break down cellular materials. Even though there are a number of types of autophagy, CMA is unique to mammals. Yet to date, the physiological role of CMA is still being deciphered.
The University of Pennsylvania Medicine researchers published their new study in the journal: Science.
Human bodies contain over 200 different types of specialized cells. All of which derive from embryonic stem (ES) cells.
Stem cells relentlessly self-renew, while retaining an ability to differentiate into any cell type in an adult animal — an ability known as pluripotency.
Researchers know cell metabolism plays a role in this process. But, it wasn't exactly clear how ES cells' keep an eternal state of self-renewal — or what ultimately signals the end to the embryonic stem cell state.
Now, a preclinical study reveals how stem cells keep CMA at low levels promoting stem cell self-renewal; and then, switch suppression off to allow CMA and other activities promoting differentiation into a specialized cell type.
"It's an intriguing discovery in the field of stem cell biology — and for development of therapies for tissue/organ regeneration. We reveal two novel ways to potentially manipulate self-renewal and differentiation in stem cells:
(1) CMA (chaperone-mediated autophagy)
(2) alpha-ketoglutarate, a metabolite controlled by CMA.
Intervening in or guiding these functions could be a powerful way to increase the efficiency of regeneration in medicine."
Xiaolu Yang PhD, Professor, Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania.
They found CMA activity is kept at a minimum due to Oct4 and Sox2 that suppress the gene LAMP2A. The LAMP2A gene provides instructions for making the protein lysosomal associated membrane protein-2 needed by CMA. Also, minimal CMA activity allows stem cells to maintain high levels of alpha-ketoglutarate, a metabolite crucial in reinforcing a cell's pluripotent state.
When it's time for differentiation, cells begin to upregulate CMA due to the reduction of Oct4 and Sox2. Augmented CMA activity leads to the degradation of key enzymes responsible for the production of alpha-ketoglutarate. This leads to a reduction in alpha-ketoglutarate levels as well as an increase in other cellular activities that promote differentiation. These findings reveal how CMA and alpha-ketoglutarate dictate the fate of embryonic stem cells.
Embryonic stem cells are often called pluripotent as they give rise to every cell type in the body — except placenta and umbilical cord.
Embryonic stem cells not only provide a superb system to study early mammalian development, but also hold great promise for regenerative therapies to treat various human disorders. The development of stem-cell based regenerative medicine therapies has rapidly increased in the last decade, with several approaches in studies shown to repair damaged heart tissue, replace cells in solid organ transplantation, and in some cases address neurological disorders.
"This newly discovered role of autophagy in the stem cell is the beginning of further investigations that could lead researchers and physician-scientists to better therapies to treat various disorders."
Xiaolu Yang PhD,
Summary
How are stemness preserved? The mechanisms underlying maintenance and self-renewal of pluripotent stem cells are yet to be determined. Both transcriptional and metabolic control have been shown to contribute to the tight regulation of stemness (1, 2). Any efforts to further understand how stemness is preserved have enormous translational potential, particularly in scenarios of unbalanced fate decisions, when lineage commitment happens at the expense of stemness maintenance, which frequently occurs in aged tissues (2, 3). In the context of embryonic stem cells (ESCs), it remains incompletely understood how these early stem cells can indefinitely propagate while maintaining pluripotency. On page 397 of this issue, Xu et al. (4) add an important missing piece, chaperone-mediated autophagy (CMA), to our understanding of how mouse ESCs remain pluripotent by unravelling a link between transcriptional and metabolic control of ESCs.
Authors
Mariana Borsa and Anna Katharina Simon.
Penn co-authors include first author Yi Xu, a post-doctoral researcher in Yang's Lab, Yang Zhang and Sixiang Yu, also in Yang's lab, Lili Guo and Ian A. Blair of the department of Systems Pharmacology and Translational Therapeutics, Mengyuan Kan of the department of Biostatistics, Epidemiology and Informatics, as well as Juan C. García-Cañaveras and Joshua D. Rabinowitz of Princeton University.
Acknowledgements
The study was supported the National Institutes of Health (R01CA182675, R01CA184867, R01CA235760, and P30ES013508, and the Department of Defense (W81XWH-15-1-0678).
Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $425 million awarded in the 2018 fiscal year.
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Aug 4 2020 2020 Fetal Timeline Maternal Timeline News
 Translucently colored embryonic stem (ES) cell (upper right) and its differentiating derivative cells (left and lower right). The small round bodies inside cells represent lysosomes, PINK color indicates cells undergoing chaperone-mediated autophagy ( CMA), a select form of autophagy only seen in mammals. CMA governs the balance between self-renewal and differentiation of ES cells. CREDIT Alex Tokarev.
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