Integrating Physiological Regulation with Stem Cell and Tissue Homeostasis

Howard Hughes Medical Institute, Life Sciences Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, MI 48109-2216, USA.
Neuron (Impact Factor: 15.05). 05/2011; 70(4):703-18. DOI: 10.1016/j.neuron.2011.05.011
Source: PubMed


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.

  • Source
    • "Medalist +C Underscores Manifestation of Diabetic Complications Under normal conditions, humans have an inherent capacity for differentiation and self-renewal to make up for the loss of functionally mature cells in a tissue, secondary to normal senescence or stress-induced apoptosis, from a pool of progenitor cells that maintain the levels of functional lineage committed and/or mature cells required for normal function (Nakada et al., 2011; Ruiz et al., 2011). However, in disease states, when this endogenous mechanism fails, complications arise requiring pharmacological intervention, cell-replacement therapy (b cells), or organ transplantation (kidney, heart etc.). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D (disease duration ≥ 50 years) with severe (Medalist +C) or absent to mild complications (Medalist -C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist -C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that worsened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.
    Full-text · Article · Aug 2015 · Cell Metabolism
  • Source
    • "A fundamental question in stem cell biology concerns the extent to which stem cells are regulated by long-range signals to ensure that stem cell function within individual tissues is integrated with the overall physiological state11. For example, stem cells in the intestine, central nervous system, and germline are regulated by insulin and nutritional status12-17. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sexually dimorphic mammalian tissues, including sexual organs and the brain, contain stem cells that are directly or indirectly regulated by sex hormones. An important question is whether stem cells also exhibit sex differences in physiological function and hormonal regulation in tissues that do not show sex-specific morphological differences. The terminal differentiation and function of some haematopoietic cells are regulated by sex hormones, but haematopoietic stem-cell function is thought to be similar in both sexes. Here we show that mouse haematopoietic stem cells exhibit sex differences in cell-cycle regulation by oestrogen. Haematopoietic stem cells in female mice divide significantly more frequently than in male mice. This difference depends on the ovaries but not the testes. Administration of oestradiol, a hormone produced mainly in the ovaries, increased haematopoietic stem-cell division in males and females. Oestrogen levels increased during pregnancy, increasing haematopoietic stem-cell division, haematopoietic stem-cell frequency, cellularity, and erythropoiesis in the spleen. Haematopoietic stem cells expressed high levels of oestrogen receptor-α (ERα). Conditional deletion of ERα from haematopoietic stem cells reduced haematopoietic stem-cell division in female, but not male, mice and attenuated the increases in haematopoietic stem-cell division, haematopoietic stem-cell frequency, and erythropoiesis during pregnancy. Oestrogen/ERα signalling promotes haematopoietic stem-cell self-renewal, expanding splenic haematopoietic stem cells and erythropoiesis during pregnancy.
    Full-text · Article · Jan 2014 · Nature
  • Source
    • "In Drosophila melanogaster fat cells, feeding activates TOR signalling and secretion of a fat-body-derived signal that regulates insulin-like peptide secretion by a subpopulation of nutritionally regulated glial cells. In turn, this insulin-like peptide activates neuroblast proliferation through PI3K/TOR signalling (Chell and Brand, 2010; Sousa- Nunes et al., 2011; Nakada et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult tissue stem cells have the ability to adjust to environmental changes and affect also the proliferation of neighboring cells, with important consequences on tissue maintenance and regeneration. Stem cell renewal and proliferation is strongly regulated during aging of the organism. Caloric restriction is the most powerful anti-aging strategy conserved throughout evolution in the animal kingdom. Recent studies relate the properties of caloric restriction to its ability in reprogramming stem-like cell states and in prolonging the capacity of stem cells to self-renew, proliferate, differentiate, and replace cells in several adult tissues. However this general paradigm presents with exceptions. The scope of this review is to highlight how caloric restriction impacts on diverse stem cell compartments and, by doing so, might differentially delay aging in the tissues of lower and higher organisms.
    Full-text · Article · Nov 2013 · Experimental gerontology
Show more