Abstract
Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent stem-cell states distinguished by relative CD34 expression: CD34High, with stemness properties (genuine state), and CD34Low, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle.
Publication types
-
Comparative Study
-
Research Support, N.I.H., Intramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Age Factors
-
Animals
-
Antigens, CD34 / metabolism*
-
Cardiotoxins / toxicity
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism
-
Cell Proliferation* / drug effects
-
Cell Proliferation* / genetics
-
Cell Self Renewal* / drug effects
-
Cell Self Renewal* / genetics
-
Cells, Cultured
-
Cellular Senescence* / drug effects
-
Cellular Senescence* / genetics
-
Forkhead Box Protein O1 / genetics
-
Forkhead Box Protein O1 / metabolism
-
Forkhead Box Protein O3 / genetics
-
Forkhead Box Protein O3 / metabolism
-
Forkhead Transcription Factors / genetics
-
Forkhead Transcription Factors / metabolism*
-
Gene Expression Regulation
-
Male
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Mice, SCID
-
Muscle, Skeletal / drug effects
-
Muscle, Skeletal / metabolism*
-
Muscle, Skeletal / pathology
-
Muscle, Skeletal / transplantation
-
Phenotype
-
Proto-Oncogene Proteins c-akt / metabolism
-
Regeneration* / drug effects
-
Regeneration* / genetics
-
Satellite Cells, Skeletal Muscle / drug effects
-
Satellite Cells, Skeletal Muscle / metabolism*
-
Satellite Cells, Skeletal Muscle / pathology
-
Satellite Cells, Skeletal Muscle / transplantation
-
Signal Transduction
-
Stem Cell Niche
Substances
-
Antigens, CD34
-
Cardiotoxins
-
Cell Cycle Proteins
-
Forkhead Box Protein O1
-
Forkhead Box Protein O3
-
Forkhead Transcription Factors
-
FoxO3 protein, mouse
-
FoxO4 protein, mouse
-
Foxo1 protein, mouse
-
Proto-Oncogene Proteins c-akt