Stem cells persist throughout life in many tissues including the central nervous system (CNS) and regenerate mature cells that are lost due to turnover, injury, and disease. However, the function of stem cells declines with age in diverse tissues including the hematopoietic system, muscle, and brain. Consistent with this, aging tissues have less repair capacity and an increased incidence of degenerative disease. These observations raise the possibility that declines in stem cell function during aging contribute to age-related morbidity and that by uncovering the mechanisms responsible for these declines we might uncover targets for therapeutic intervention. The forebrain lateral ventricle subventricular zone (SVZ) contains stem cells that engage in neurogenesis throughout adult life. The frequency of stem cells, their self-renewal potential, mitotic activity in vivo, and rate of neurogenesis all decline with age, but the physiological mechanisms responsible for these declines are only beginning to be identified. During the prior funding period we discovered that Ink4a expression increases with age in these stem cells. Ink4a encodes a cyclin-dependent kinase inhibitor, p16Ink4a, that impairs proliferation and promotes cellular senescence by activating Rb. Deletion of Ink4a partially rescues the decline in stem cell frequency, mitotic activity, and neurogenesis in aging mice without affecting young mice. In preliminary studies we have discovered that the Alternative reading frame (Arf) at the Ink4a/Arf locus is not detectable in fetal and young adult stem cells but increases in expression with age and negatively regulates stem cell frequency and function. Arf encodes the p19Arf tumor suppressor, which impairs proliferation and promotes cellular senescence by promoting p53 function. This raises the question of whether Arf contributes to the decline in stem cell function with age.
In Aim 1 we will test whether conditional deletion of Arf from aging neural stem cells partially rescues the decline in stem cell frequency and function during aging. A second question is what regulates the increase in Ink4a and Arf expression with age. We have discovered that the high mobility group transcriptional regulator, Hmga2, is expressed by fetal and young adult, but not old adult stem cells. Hmga2 increases the frequency and function of neural stem cells in fetal and young adult mice by negatively regulating Ink4a and Arf expression.
In Aim 2 we will test whether Hmga2 negatively regulates Ink4a/Arf expression by repressing the JunB transcription factor and whether changes in JunB expression also regulate neural stem cell aging. Finally, we have discovered that the microRNA let-7b, which inhibits Hmga2 expression, increases its expression with age in neural stem/progenitor cells.
In Aim 3 we will test whether the decline in Hmga2 expression during aging is caused by the increase in let-7 function. Our experiments offer the opportunity to unravel a novel pathway in which let-7b, Hmga2, JunB, p16Ink4a, and p19Arf regulate the age-related decline in stem cell function and neurogenesis in the mammalian CNS.

Public Health Relevance

Aging tissues exhibit reduced stem cell function, reduced regenerative capacity, and an increased incidence of degenerative disease. We have identified a series of genes that function as part of a pathway that reduces stem cell function and tissue regenerative capacity during aging. By better understanding these mechanisms we will gain new insights into why aging tissues have reduced regenerative capacity as well as therapeutic strategies to enhance regeneration.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Neurogenesis and Cell Fate Study Section (NCF)
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Wise, Bradley C
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Liao, Chung-Ping; Booker, Reid C; Morrison, Sean J et al. (2017) Identification of hair shaft progenitors that create a niche for hair pigmentation. Genes Dev 31:744-756
Shimada, Issei S; Acar, Melih; Burgess, Rebecca J et al. (2017) Prdm16 is required for the maintenance of neural stem cells in the postnatal forebrain and their differentiation into ependymal cells. Genes Dev 31:1134-1146
Agathocleous, Michalis; Meacham, Corbin E; Burgess, Rebecca J et al. (2017) Ascorbate regulates haematopoietic stem cell function and leukaemogenesis. Nature 549:476-481
Zhou, Bo O; Yu, Hua; Yue, Rui et al. (2017) Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat Cell Biol 19:891-903
Lin, Haotian; Ouyang, Hong; Zhu, Jie et al. (2016) Lens regeneration using endogenous stem cells with gain of visual function. Nature 531:323-8
Bednar, Filip; Schofield, Heather K; Collins, Meredith A et al. (2015) Bmi1 is required for the initiation of pancreatic cancer through an Ink4a-independent mechanism. Carcinogenesis 36:730-8
Wu, Linwei; Nguyen, Liem H; Zhou, Kejin et al. (2015) Precise let-7 expression levels balance organ regeneration against tumor suppression. Elife 4:e09431
Mich, John K; Signer, Robert Aj; Nakada, Daisuke et al. (2014) Prospective identification of functionally distinct stem cells and neurosphere-initiating cells in adult mouse forebrain. Elife 3:e02669
Burgess, R J; Agathocleous, M; Morrison, S J (2014) Metabolic regulation of stem cell function. J Intern Med 276:12-24
Signer, Robert A J; Magee, Jeffrey A; Salic, Adrian et al. (2014) Haematopoietic stem cells require a highly regulated protein synthesis rate. Nature 509:49-54

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