Neural Stem and Progenitor Cells Retain Their Potential for Proliferation and Differentiation into Functional Neurons Despite Lower Number in Aged Brain

Ahlenius, Henrik; Visan, Violeta; Kokaia, Mérab; Lindvall, Olle; Kokaia, Zaal

doi:10.1523/jneurosci.6003-08.2009

Cited by 188 publications

(211 citation statements)

References 40 publications

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“…Remarkably, however, we did not detect any significant difference in the efficiency of reprogramming or function of iN cells from fibroblasts derived from young or aging mice. This finding is in accordance with the finding that the neuronal differentiation capacity of endogenous neural stem cells did not change from adult to aged animals, and that once mature neurons had formed, there were no detectable differences in their function (21).…”

Section: Discussionsupporting

confidence: 92%

FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice

Ahlenius

Chanda

Webb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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We and others have shown that embryonic and neonatal fibroblasts can be directly converted into induced neuronal (iN) cells with mature functional properties. Reprogramming of fibroblasts from adult and aged mice, however, has not yet been explored in detail. The ability to generate fully functional iN cells from aged organisms will be particularly important for in vitro modeling of diseases of old age. Here, we demonstrate production of functional iN cells from fibroblasts that were derived from mice close to the end of their lifespan. iN cells from aged mice had apparently normal active and passive neuronal membrane properties and formed abundant synaptic connections. The reprogramming efficiency gradually decreased with fibroblasts derived from embryonic and neonatal mice, but remained similar for fibroblasts from postnatal mice of all ages. Strikingly, overexpression of a transcription factor, forkhead box O3 (FoxO3), which is implicated in aging, blocked iN cell conversion of embryonic fibroblasts, whereas knockout or knockdown of FoxO3 increased the reprogramming efficiency of adult-derived but not of embryonic fibroblasts and also enhanced functional maturation of resulting iN cells. Hence, FoxO3 has a central role in the neuronal reprogramming susceptibility of cells, and the importance of FoxO3 appears to change during development.aging | reprogramming | induced neuronal cells R ecent advances in direct reprogramming have demonstrated the feasibility of converting fibroblasts and other terminally differentiated lineages into induced neuronal (iN) cells (1-8). iN cells display elaborate morphologies typical of neurons, express pan-neuronal markers, exhibit hallmarks of functional neurons in that they fire action potentials and form abundant synapses, and, thus, provide a great opportunity for studying the cellular phenotypes of disease-associated genetic mutations (9). To date, most studies used embryonic or early postnatal fibroblasts for reprogramming purposes, but for clinical applications, and in particular for modeling age-related neurodegenerative diseases, it would be preferable to generate iN cells from adult and aged animals.Lineage conversion from aged cells is often challenging, probably due to epigenetic changes during aging. For example, aging has been shown to impair conversion of somatic cells into induced pluripotent stem cells (3,(10)(11)(12). A recent elegant paper demonstrated successful conversion of fibroblasts from old individuals, but cellular properties were not compared between different age groups (13). In embryonic fibroblasts, overexpression of three transcription factors, Brn2, Ascl1, and Myt1l (BAM), efficiently generates iN cells with mature, functional properties within 2 wk (1). Genomic studies and chromatin characterization experiments of fibroblasts shortly after BAM factor expression revealed unique pioneer factor properties of Ascl1, which led to our observation that Ascl1 alone is sufficient to generate functional iN cells, albeit slower and with lower efficiency tha...

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Section: Discussionsupporting

confidence: 92%

FoxO3 regulates neuronal reprogramming of cells from postnatal and aging mice

Ahlenius

Chanda

Webb

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Aged SVZ NSPCs form smaller neurospheres and adherent colonies compared with young adult NSPCs, and this correlates with their decreased proliferation capacity in vitro (Ahlenius et al., 2009; Corenblum et al., 2016; Daynac et al., 2014, 2016; L'Episcopo et al., 2013; Zhu et al., 2014). We also observed a proliferation defect in NSPCs derived from the aged mice (Figures S1B,C).…”

Section: Resultsmentioning

confidence: 99%

“…Aging is associated with reduced neurogenesis in the mouse SVZ and SGZ (Encinas et al., 2011; Enwere et al., 2004; Lugert et al., 2010; Luo, Daniels, Lennington, Notti & Conover, 2006), which might lead to decreased olfactory function and cognitive hippocampus‐dependent impairment (Goncalves et al., 2016; Lledo & Valley, 2016). This age‐associated neurogenic decline appears to be caused both by a depletion in the NSPC pool of the aged niche (Ahlenius, Visan, Kokaia, Lindvall & Kokaia, 2009; Bouab, Paliouras, Aumont, Forest‐Berard & Fernandes, 2011; Corenblum et al., 2016; Enwere et al., 2004; Luo et al., 2006; Maslov, Barone, Plunkett & Pruitt, 2004; Molofsky et al., 2006; Stoll et al., 2011) and by the decreased capacity of the remaining NSPCs to sustain proliferation and neuronal differentiation, as revealed by in vitro studies (Ahlenius et al., 2009; Apostolopoulou et al., 2017; Corenblum et al., 2016; Daynac, Morizur, Chicheportiche, Mouthon & Boussin, 2016; Daynac et al., 2014; L'Episcopo et al., 2013; Shi et al., 2017; Zhu et al., 2014). NSPCs undergo cell autonomous age‐related changes that affect intracellular molecular pathways, including the altered expression of telomerase and cell cycle regulators, which have been linked to the decline in NSPC proliferation upon aging (Caporaso, Lim, Alvarez‐Buylla & Chao, 2003; Molofsky et al., 2006; Nishino, Kim, Chada & Morrison, 2008).…”

Section: Introductionmentioning

confidence: 99%

Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age‐associated neurogenic decline

et al. 2018

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SummaryAdult neurogenesis declines with aging due to the depletion and functional impairment of neural stem/progenitor cells (NSPCs). An improved understanding of the underlying mechanisms that drive age‐associated neurogenic deficiency could lead to the development of strategies to alleviate cognitive impairment and facilitate neuroregeneration. An essential step towards this aim is to investigate the molecular changes that occur in NSPC aging on a genomewide scale. In this study, we compare the transcriptional, histone methylation and DNA methylation signatures of NSPCs derived from the subventricular zone (SVZ) of young adult (3 months old) and aged (18 months old) mice. Surprisingly, the transcriptional and epigenomic profiles of SVZ‐derived NSPCs are largely unchanged in aged cells. Despite the global similarities, we detect robust age‐dependent changes at several hundred genes and regulatory elements, thereby identifying putative regulators of neurogenic decline. Within this list, the homeobox gene Dbx2 is upregulated in vitro and in vivo, and its promoter region has altered histone and DNA methylation levels, in aged NSPCs. Using functional in vitro assays, we show that elevated Dbx2 expression in young adult NSPCs promotes age‐related phenotypes, including the reduced proliferation of NSPC cultures and the altered transcript levels of age‐associated regulators of NSPC proliferation and differentiation. Depleting Dbx2 in aged NSPCs caused the reverse gene expression changes. Taken together, these results provide new insights into the molecular programmes that are affected during mouse NSPC aging, and uncover a new functional role for Dbx2 in promoting age‐related neurogenic decline.

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“…73 Additionally, young and old rodent brains yield similar numbers of neurospheres. 74 Furthermore, proliferating and differentiating NSC/NPCs from each of these groups exhibited similar input resistance and resting V mem , 74 suggesting similar types and levels of ion channel expression in aged brain. Focal cerebral ischemia following experimental stroke, induces similar magnitudes of neurogenesis in young (3 mo) and old (15 mo) rats.…”

Section: Resultsmentioning

confidence: 99%