Stem Cell Aging? Blame It on the Niche

Abstract

The molecular basis for the neural stem cell quiescence-to-activation transition has become an important focus in the study of adult neurogenesis. Recently in Cell, Kalamakis et al. (2019) show that aged neural stem cells face greater barriers to exiting quiescence, imposed by the niche through inflammation and altered Wnt signaling.Neural stem cells (NSCs) generate newborn neurons in a process referred to as neurogenesis, supporting cognitive functions in the brain throughout life in at least two areas: the ventricular-subventricular zone (V-SVZ) of the lateral ventricles and the subgranular zone of the hippocampus. However, neurogenesis dramatically decreases with age, coinciding with an array of age-related pathologies in the brain. Recently, many studies have identified alterations in how stem cells throughout the body enter and exit quiescence as a key feature of their dysfunction with aging and have begun to explore the molecular mechanisms driving quiescence. In NSCs, quiescence is now understood to be driven largely by extrinsic signals from the niche and involves a shift in metabolism and proteostasis (Knobloch et al., 2017;Leeman et al., 2018;Shin et al., 2015;Silva-Vargas et al., 2016). In a recent Cell study, Kalamakis et al. (2019) use mathematical modeling and numerous in vitro and in vivo experiments to suggest that an increase in quiescence driven by the aged niche is the major factor driving the decrease in neurogenesis with aging in the V-SVZ.This same group has modeled the agedependent decline in neurogenesis in the hippocampus, concluding that with age, hippocampal NSCs remain quiescent for longer periods of time (Ziebell et al., 2018). In the Kalamakis et al. (2019) study, the authors used a similar but more simplistic mathematical model and also found that time in quiescence increased with aging in V-SVZ NSCs. To validate their prediction, they treated young and old mice with temozolomide (TMZ), a chemotherapeutic drug that kills activated NSCs (aNSCs) and leads to activation of quiescent NSCs (qNSCs). Following a period of recovery after TMZ treatment, they found that whereas young animals were able to fully recover their aNSC number, old animals were able to recover only half of their original aNSC number, demonstrating that old NSCs were not exiting quiescence at the same rate as young NSCs.To identify what was driving the increase in quiescence in old NSCs, the authors performed live-cell imaging on freshly sorted NSCs in vitro from a young or old mouse brain and found that both ages had similar potential to differentiate and proliferate. Further, when the authors performed principal component analysis on RNA sequencing in young and old qNSCs and aNSCs, they discovered that NSCs were transcriptionally similar between ages. These data suggested that NSCs intrinsically age very little and that the aged niche is largely responsible for the increase in quiescence in the aged V-SVZ.Recently, several studies have identified the niche as an important component regulating qNSC activation. Silva-...

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Corroborating our earlier findings, a number of recent studies have highlighted the critical importance of WβC crosstalk with survival and inflammatory pathways in inciting neurogenesis and neurorepair Kalamakis et al, 2019;Kase, Otsu, Shimazaki, & Okano, 2019;Mishra et al, 2019;Morrow & Moore, 2019;Ray et al, 2018;Singh, Mishra, Bharti, et al, 2018b;Singh, Mishra, Mohanbhai, et al, 2018a;Singh, Mishra, & Shukla, 2016).…”

Robo4 inhibits gamma radiation-induced permeability of a murine microvascular endothelial cell by regulating the junctions

“…Studies have shown that VE-cadherin is a major modulator of microvascular endothelial permeability in the bone marrow [43]. Antibody-mediated inhibition of VE-cadherin led to increased permeability in both arterioles and sinusoids of the bone marrow under normal conditions and upon low-dose irradiation [44,45]. Silencing Robo4 in microvascular ECs, we observed a substantial decrease in the expression of total VE-cadherin following irradiation, suggesting a potential role of Robo4 in regulating AJs.…”

Age-dependent structural and morphological changes of the stem cell niche disrupt spatiotemporal regulation of stem cells and drive tissue disintegration

“…Stem cells can remain activated, which are essentially immortal and rejuvenated over the organismal lifecycle, or become quiescent upon the completion of development, exhibiting a progressive decline in their functions and frequency, which has been considered to be aging (Charville & Rando 2011; Devaraj et al 2021; Pan et al 2007; Rossi et al 2008). However, recent studies suggest that stem cells age very little intrinsically, and extrinsic factors such as the microenvironment are largely responsible for the age-dependent stem cell decline (Kalamakis et al 2019; Morrow & Moore 2019). Unraveling the molecular mechanisms of age-dependent stem cell decline is crucial to advancing therapeutics to delay tissue deterioration, reverse the aging process, and alleviate age-related diseases.…”

“…A major extrinsic factor for stem cell function is the stem cell niche, which is located adjacent to stem cells and provides a microenvironment to them. The niches are often specialized, somatic cells and hence are not rejuvenated but experience the aging process, including a structural or functional decline (Jasper & Kennedy 2012; Morrow & Moore 2019; Ryu et al 2006; Wallenfang 2007). For example, the stem cell niche in the female Drosophila gonad progressively loses physical contact with the stem cells as it ages (Pan et al 2007), and the niche signaling from the neural stem cell niche decreases during aging, inhibiting the stem cells from exiting the quiescent state to repopulate upon injury (Kalamakis et al 2019; Morrow & Moore 2019).…”

“…The niches are often specialized, somatic cells and hence are not rejuvenated but experience the aging process, including a structural or functional decline (Jasper & Kennedy 2012; Morrow & Moore 2019; Ryu et al 2006; Wallenfang 2007). For example, the stem cell niche in the female Drosophila gonad progressively loses physical contact with the stem cells as it ages (Pan et al 2007), and the niche signaling from the neural stem cell niche decreases during aging, inhibiting the stem cells from exiting the quiescent state to repopulate upon injury (Kalamakis et al 2019; Morrow & Moore 2019). Niche aging has been thought to be a major driver of age-dependent stem cell loss and its functional decline (Brunet et al 2022; Goodell & Rando 2015; Navarro Negredo et al 2020).…”