Stem cell function
Stem cell function
Stem cells are emerging as one of the fundamental underpinnings of tissue biology. They allow blood, bone, gametes, epithelia, nervous system, muscle, and myriad other tissues to be replenished by fresh cells throughout life. Stem cells maintain tissue homeostasis over time by regularly replacing damaged or lost cells. Stem cells share two defining properties—pluripotency and self-renewal. Stem cells are pluripotent in that they give rise to all cells within a given tissue (or to all cells within the body). Stem cells also have the capacity to generate with each division, another cell with the stem cell program. This stem cell property is known as self-renewal and enables the organism to maintain a stem cell pool throughout its lifetime. The function of stem cells is known to decline with age.
Adult stem cells are known to be mostly quiescent and to rarely enter cell cycle. It has been postulated that quiescence protects stem cells from incurring damage during cell division and plays a necessary role in their lifetime maintenance. Nonetheless, when faced with major tissue loss or damage, stem cells exit their quiescent state and enter the cell cycle to proliferate and generate large numbers of differentiated progenies. These properties may be shared by cancer stem cells.
Reactive oxygen species (ROS) are being increasingly implicated in the physiological regulation of critical developmental processes, including the emergence of embryonic blood stem cells. A potential model may be that ROS function as a stem cell rheostat by sensing and translating environmental cues into a cellular response to balance cellular output (function) with cellular input (e.g., nutrients, cytokines). Stem cells, in particular, may take advantage of redox regulation to coordinate cell cycle with differentiation as a means of holding their stem cell fate in check, while ensuring homeostasis.
As a result of a largely quiescent state, stem cells in aged tissues experience long-term exposure to genotoxic assaults, from both endogenous and exogenous sources, and an apparent accumulation of DNA damage in aged stem cells has been noted in several studies. For example, aged HSCs and muscle stem cells (also called satellite cells) show an increased number of nuclear foci that stain for the phosphorylated form of the variant histone H2A.X (γH2A.X), which serves as a marker of DNA double-strand breaks. Genotoxic lesions could cause stem cell senescence or apoptosis and might directly affect gene regulation, leading to alterations in stem cell self-renewal and differentiation. Some studies suggest that the ensuing loss of homeostasis in aging tissues might further create a microenvironment that favors the selection of stem cells with higher self-renewal but also neoplastic potentials.
Defects in proteostasis commonly lead to aberrant folding, toxic aggregation and accumulation of damaged proteins, which can in turn cause cellular damage and tissue dysfunction68. Indeed, age is one of the main risk factors for most diseases associated with protein misfolding, including neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. As regards stem cell function, proteostasis has been implicated as an important determinant of stem cell maintenance through studies in HSCs showing that deletion of autophagy-related gene 7 (Atg7) increases ROS levels and depletes HSCs. Proteostasis was also shown to be fundamental to maintenance of identity in human embryonic stem cells (hESCs). FOXO4 promotes proteasome activity in hESCs by regulating PSDM11 expression, thereby encouraging proteostasis and maintenance of pluripotency markers, such as POU5F1, OCT4, NANOG, SOX2, UTF1, DPPA4, DPPA2, ZFP42 and TERT.
Age-dependent reductions in mitochondrial function leading to respiratory chain dysfunction have been observed in several cell systems and have been thought to result largely from accumulation of mutations in mitochondrial DNA (mtDNA). Nutrient sensing and energy homeostasis have been implicated as connecting mitochondrial function and longevity. In HSCs, an age-dependent decrease in nutrient uptake capacity has been observed with age, implying that the nutrient sensing pathway is involved in stem cell aging.
Stem cells reside in specialized microenvironments, called niches, that promote their maintenance and regulate their functions. Aging of niche cells and age-dependent alterations in the acellular components of stem cell niches can cause maladaptive changes in stem cell function.