Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration

Porpiglia, Ermelinda; Mai, Thach; Kraft, Peggy E.; Holbrook, Colin; Morrée, Antoine de; Gonzalez, Veronica D.; Hilgendorf, Keren I.; Frésard, Laure; Trejo, Angelica; Bhimaraju, Sriram; Jackson, Peter K.; Fantl, Wendy J.; Blau, Helen M.

doi:10.1016/j.stem.2022.10.009

“…Studies based on human and mouse models have revealed numerous hallmarks accompanying or driving MuSC senescence. Intrinsically, increased p16 fragmentation (Baker et al, 2022;Tezze et al, 2017), reduced autophagy (García-Prat et al, 2016) and functional heterogeneity (Tierney et al, 2018), loss of ciliation (Palla et al, 2022), decreased CD34 (García-Prat et al, 2020), FOXO (García-Prat et al, 2020;Jing et al, 2022) and Notch (Carlson et al, 2008;Conboy et al, 2003) signaling, elevated activation of CD47 (Porpiglia et al, 2022) and JAK-STAT signaling (Price et al, 2014;Tierney et al, 2014), have all been proven to be the prominent detriments to MuSC stemness and cause regenerative failure. Aging in the MuSC niche contributes another core source releasing secreted factors that drive MuSC senescence.…”

Section: Cellular Alterationsmentioning

confidence: 99%

“…Hi subpopulation of MuSCs has also been identified, which is increased in aged mice and found to impair muscle regeneration via thrombospondin-1/CD47 signaling (Kania et al, 1995;Porpiglia et al, 2022). Except for the subpopulation changes, MuSC quiescence is generally disrupted, and their self-renewal capabilities are remarkably compromised during aging.…”

Section: Cd47mentioning

confidence: 99%

Biomarkers of aging

Bao

¹

,

Cao

²

,

Chen

³

et al. 2023

Sci. China Life Sci.

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Aging biomarkers are a combination of biological parameters to (i) assess age-related changes, (ii) track the physiological aging process, and (iii) predict the transition into a pathological status. Although a broad spectrum of aging biomarkers has been developed, their potential uses and limitations remain poorly characterized. An immediate goal of biomarkers is to help us answer the following three fundamental questions in aging research: How old are we? Why do we get old? And how can we age slower? This review aims to address this need. Here, we summarize our current knowledge of biomarkers developed for cellular, organ, and organismal levels of aging, comprising six pillars: physiological characteristics, medical imaging, histological features, cellular alterations, molecular changes, and secretory factors. To fulfill all these requisites, we propose that aging biomarkers should qualify for being specific, systemic, and clinically relevant. Supporting Information The supporting information is available online at 10.1007/s11427-023-2305-0. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.

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“…A previous study showed that CD47 deficient mice had enhanced treadmill endurance and their skeletal muscle had greater number of mitochondria as compared to wild type mice 16 . CD47 also plays a role in regulating aged muscle stem cell regeneration capacity 24 . In the current study, we found that CD47ASO treated mice had increased physical activity demonstrated by increased voluntary wheel running distance in metabolic cages.…”

Section: Discussionmentioning

confidence: 99%

CD47 antisense oligonucleotide treatment attenuates obesity and its-associated metabolic dysfunction

Gwag

¹

,

Liu

²

,

Ma

³

et al. 2023

Sci Rep

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Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its-associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. Mechanistically, CD47ASO treatment increased mice physical activity and energy expenditure, contributing to weight loss and improved metabolic outcomes in obese mice. Collectively, these findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.

show abstract

“…A previous study showed that CD47 de cient mice had enhanced treadmill endurance and their skeletal muscle had greater number of mitochondria as compared to wild type mice 16 . CD47 also plays a role in regulating aged muscle stem cell regeneration capacity 24 . In the current study, we found that CD47ASO treated mice had increased physical activity demonstrated by increased voluntary wheel running distance in metabolic cages.…”

Section: Discussionmentioning

confidence: 99%

CD47 antisense oligonucleotide treatment attenuates obesity and its-associated metabolic dysfunction

Gwag

¹

,

Liu

²

,

Ma

³

et al. 2023

Preprint

0

View full text Add to dashboard Cite

Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its-associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. Mechanistically, CD47ASO treatment increased mice physical activity and energy expenditure, contributing to weight loss and improved metabolic outcomes in obese mice. Collectively, these findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.

show abstract

Elevated CD47 is a hallmark of dysfunctional aged muscle stem cells that can be targeted to augment regeneration

Cited by 29 publications

References 79 publications

Biomarkers of aging

Biomarkers of aging

CD47 antisense oligonucleotide treatment attenuates obesity and its-associated metabolic dysfunction

CD47 antisense oligonucleotide treatment attenuates obesity and its-associated metabolic dysfunction

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