Integrating physiological regulation with stem cell and tissue homeostasis

Abstract

Stem cells are uniquely able to self-renew, to undergo multilineage differentiation, and to persist throughout life in a number of tissues. Stem cells are regulated by a combination of shared and tissue-specific mechanisms and are distinguished from restricted progenitors by differences in transcriptional and epigenetic regulation. Emerging evidence suggests that other aspects of cellular physiology, including mitosis, signal transduction, and metabolic regulation, also differ between stem cells and their progeny. These differences may allow stem cells to be regulated independently of differentiated cells in response to circadian rhythms, changes in metabolism, diet, exercise, mating, aging, infection, and disease. This allows stem cells to sustain homeostasis or to remodel relevant tissues in response to physiological change. Stem cells are therefore not only regulated by short-range signals that maintain homeostasis within their tissue of origin, but also by long-range signals that integrate stem cell function with systemic physiology.

Figure 1. Some mechanisms promote stem cell self-renewal in multiple tissues but do not promote the proliferation of all progenitors

A. A schematic depiction of stem cells from two different tissues giving rise to their respective restricted progenitors and differentiated cells. The yellow nucleus denotes that some transcriptional and epigenetic mechanisms that cell-intrinsically promote stem cell maintenance are conserved across tissues; however these mechanisms are not necessarily required by restricted progenitors or differentiated cells from the same tissues. Examples of this include Bmi-1, Sox17, Prdm16, and Hmga2 (see text for details and references). B. Stem cells also depend upon extrinsic short-range signals from the niche (yellow cells) for their maintenance. Niches in different tissues and different species often employ similar strategies, and even similar secreted factors, to promote stem cell maintenance. Stem cells often depend upon Wnt, Notch, and/or BMP ligands secreted by the niche for their maintenance. Exposure to this short-range signal from the niche distinguishes stem cells (yellow nucleus) from progenitors fated to differentiate and the size of the niche determines the number of stem cells in the tissue. Cells displaced from the niche by cell division or competition are fated to differentiate (Fuller and Spradling, 2007; Morrison and Spradling, 2008). C. Stem cells are also extrinsically regulated by long-range signals that reflect nutritional status, oxygen level, hormonal status, or other physiological changes.

Figure 2. Stem cell self-renewal mechanisms change with age

A. A pathway of tumor suppressors (red) and proto-oncogenes (green) that control stem cell self-renewal and that change in expression with age (Nishino et al., 2008). Arrows indicate whether expression increases or decreases with age in stem cells. B. The balance between proto-oncogenic signals and gate-keeping tumor suppressor signals changes with age within stem cells (Levi and Morrison, 2009). Proto-oncogenic signals dominate during fetal development when stem cells divide rapidly, and some gate-keeping tumor suppressor mechanisms that are critical during adulthood are not competent to negatively regulate division in fetal stem cells. Proto-oncogenes and gate-keeping tumor suppressors come into balance in young adult stem cells, which are often quiescent but remain able to enter cycle to regenerate tissues after injury. Gate-keeping tumor suppressors, such as p16^Ink4a, predominate in aging stem cells, which exhibit less regenerative potential. C. The changing balance between proto-oncogenes and tumor suppressors allows stem cells to change their properties throughout life in a way that mirrors changing tissue demands. Tissue growth and regenerative capacity decline over time while cancer incidence increases. The increasing tumor suppressor expression during aging may attenuate the increasing cancer incidence in aging tissues at the cost of reducing tissue regenerative capacity. Increasing expression of the gate-keeping tumor suppressors p16^Ink4a and p19^Arf increases mouse lifespan through mechanisms beyond reducing cancer incidence (Matheu et al., 2009). This suggests it is advantageous to negatively regulate the proliferation of some cells in aging tissues, despite the consequent reduction in stem cell function and tissue regeneration. D. Un-repaired DNA damage (red crosses) accumulates with age to a greater extent in stem cells as compared to restricted progenitors (Rossi et al., 2007). Cell-extrinsic factors also modulate stem cell aging. Muscle satellite cell function declines with age as these cells are exposed to a decreased level of Notch ligands and increased levels of Wnt and TGFβ (Brack et al., 2007; Carlson et al., 2008; Conboy et al., 2003; Conboy et al., 2005; Liu et al., 2007).

Figure 3. Signaling pathways that regulate energy and oxygen metabolism in stem cells

Various growth factors activate PI-3kinase through their receptors, leading to activation of Akt (Engelman et al., 2006). Akt activation leads to mTORC1 activation, which promotes protein translation and lipid synthesis. The Lkb1-AMPK pathway becomes activated upon energy stress and inhibits the mTORC1 pathway by activating TSC (Shackelford and Shaw, 2009). Akt also negatively regulates FoxO transcription factor function. FoxO transcription factors promote the expression of enzymes that detoxify ROS (Salih and Brunet, 2008). Other transcriptional/epigenetic regulators, such as Bmi1 and Prdm16, also regulate oxidative stress and mitochondrial function. HIF transcription factors are stabilized in hypoxia by the inhibition of von Hippel Lindau (VHL)-mediated degradation. HIF promotes glucose uptake and glycolysis to adapt to hypoxia. Red ovals indicate tumor suppressors, green ovals indicate proto-oncogenes, and yellow ovals indicate proteins whose role in tumorigenesis is not clear.

Figure 4. Integrating stem cell function with systemic physiology

Physiological changes experienced by animals cause changes in stem cell function that lead to adaptive changes in tissue growth and remodeling. Stem cell function is modulated by long-range extrinsic signals that reflect changes in nutrition (A), circadian regulation (B), hormones (C, D), and oxygen tension (E). These signals sometimes act directly on stem cells and sometimes act on niche cells to indirectly modulate stem cell function (see text for details and references). The CNS is integral to the coordination of many physiological changes through neural activity (B) and the secretion of hormones (D). A. Stem cell function is modulated by insulin and other signals that reflect nutritional status. B. Stem cells are regulated by circadian rhythms generated centrally in the suprachiasmatic nucleus (SCN) of the brain and conveyed through the sympathetic nervous system (SNS). C, D. Sexual maturation, mating, and pregnancy can influence stem cell function by changing the expression of hormones from the gonads (C) and the pituitary gland (D). E. Physiological changes also modulate stem cell function by altering oxygen levels and systemic levels of cytokines and growth factors in the blood. Dashed arrows indicate factors secreted from the indicated organ that act on stem cells and their niches in multiple target tissues (green and orange).