Loss of stem cell regenerative capacity within aged niches

Abstract

SummaryThis work uncovers novel mechanisms of aging within stem cell niches that are evolutionarily conserved between mice and humans and affect both embryonic and adult stem cells. Specifically, we have examined the effects of aged muscle and systemic niches on key molecular identifiers of regenerative potential of human embryonic stem cells (hESCs) and post-natal muscle stem cells (satellite cells). Our results reveal that aged differentiated niches dominantly inhibit the expression of Oct4 in hESCs and Myf-5 in activated satellite cells, and reduce proliferation and myogenic differentiation of both embryonic and tissue-specific adult stem cells (ASCs). Therefore, despite their general neoorganogenesis potential, the ability of hESCs, and the more differentiated myogenic ASCs to contribute to tissue repair in the old will be greatly restricted due to the conserved inhibitory influence of aged differentiated niches. Significantly, this work establishes that hESC-derived factors enhance the regenerative potential of both young and, importantly, aged muscle stem cells in vitro and in vivo ; thus, suggesting that the regenerative outcome of stem cell-based replacement therapies will be determined by a balance between negative influences of aged tissues on transplanted cells and positive effects of embryonic cells on the endogenous regenerative capacity. Comprehensively, this work points toward novel venues for in situ restoration of tissue repair in the old and identifies critical determinants of successful cell-replacement therapies for aged degenerating organs.

Epigenetic regulation of aging stem cells

“…During aging in rodents and humans, muscle satellite cells also display impaired activation following insults, resulting in decreased muscle regeneration after injury or exercise (Conboy et al, 2003;Carlson and Conboy, 2007;Carlson et al, 2008Carlson et al, , 2009. Muscle satellite cells isolated from aged rats produce fewer progeny when propagated in vitro, suggesting impaired proliferative capacity outside the niche (Schultz and Lipton, 1982).…”

The Hydra model: disclosing an apoptosis-driven generator of Wnt-based regeneration

“…This variability actually reflects the constraints applied by both the developmental status of the organism and the pre-injury homeostatic conditions of the injured tissue on this module. Indeed the length of this module is directly influenced by the intensity of the developmental and aging processes on-going in the regenerating organism 84,85 : basically no need for a bridge between wound healing and re-development in the embryo, but a bridge that gets longer with the closing of the developmental processes and the progressive appearance of aging in the adult. Also the homeostatic status at the time and place of injury defines which cellular tools can be activated upon injury.…”

Age‐related changes in miR‐143‐3p:Igfbp5 interactions affect muscle regeneration

“…Age‐related changes in muscle are thought to depend on a number of changes including mitochondrial production of reactive oxygen species (Jackson & McArdle, 2011), changes in muscle niche (Carlson & Conboy, 2007) and intracellular changes, such as changes in gene expression (Jejurikar et al ., 2006). Regeneration of adult skeletal muscle is largely dependent on satellite cell population (Morgan & Partridge, 2003).…”