Ependyma‐expressed CCN 1 restricts the size of the neural stem cell pool in the adult ventricular‐subventricular zone

Abstract

Adult neural stem cells (NSCs) reside in specialized niches, which hold a balanced number of NSCs, their progeny, and other cells. How niche capacity is regulated to contain a specific number of NSCs remains unclear. Here, we show that ependyma‐derived matricellular protein CCN1 (cellular communication network factor 1) negatively regulates niche capacity and NSC number in the adult ventricular–subventricular zone (V‐SVZ). Adult ependyma‐specific deletion of Ccn1 transiently enhanced NSC proliferation and reduced neuronal differentiation in mice, increasing the numbers of NSCs and NSC units. Although proliferation of NSCs and neurogenesis seen in Ccn1 knockout mice eventually returned to normal, the expanded NSC pool was maintained in the V‐SVZ until old age. Inhibition of EGFR signaling prevented expansion of the NSC population observed in CCN1 deficient mice. Thus, ependyma‐derived CCN1 restricts NSC expansion in the adult brain to maintain the proper niche capacity of the V‐SVZ.

Isolation of neural stem and oligodendrocyte progenitor cells from the brain of live rats

“…Milking is based on the targeted damage of the ependyma, a cellular element of the NSC niche known to be important for providing a structural barrier toward the ventricular space (as we confirm here), but also as a regulator of NSPC function (Kazanis and ffrench-Constant, 2012;Lim et al, 2000;Nascimento et al, 2018;Wu et al, 2020). Our data confirm and extend recent observations in GemC1 knockout mice in which ependyma fails to form.…”

Assessing the Role of Ependymal and Vascular Cells as Sources of Extracellular Cues Regulating the Mouse Ventricular-Subventricular Zone Neurogenic Niche

“…Recent studies indicate that some of these signals may be important to restrict the expansion of the adult V-SVZ NSC pool, which may help to maintain its long-term neurogenic capacity. In particular, the secreted ECM-associated protein CCN1 (cellular communication network factor 1), which is involved in the regulation of cell proliferation by interacting with integrins, is specifically expressed in ependymal cells in the adult mouse V-SVZ ( Wu et al, 2020 ). Conditional CCN1 inactivation in these cells caused transient NSC expansion, leading to an increase in the density of NSCs and pinwheel units that persisted in aged mice.…”

“…Four weeks after CCN1 deletion, however, the amounts of aNSCs, TAPs and newborn neurons were similar to those present in control mice. This suggests that CCN1-deficient NSCs rapidly returned to quiescence after their initial activation and expansion, although the larger NSC pool of the CCN1-deficient V-SVZ conferred stronger regeneration capacity upon pharmacological depletion of the proliferating NSPC population ( Wu et al, 2020 ). To elucidate the signaling pathways mediating the effects of ependymal CCN1 inactivation on NSCs, Wu and colleagues performed treatments with pharmacological inhibitors of epidermal growth factor receptor (EGFR) or with blocking antibodies against integrin α6β1.…”

“…To elucidate the signaling pathways mediating the effects of ependymal CCN1 inactivation on NSCs, Wu and colleagues performed treatments with pharmacological inhibitors of epidermal growth factor receptor (EGFR) or with blocking antibodies against integrin α6β1. These proteins are expressed in V-SVZ NSCs, where they are involved either in NSC proliferation (EGFR) ( Cochard et al, 2021 ), or in CCN1 binding (integrin α6β1) ( Wu et al, 2020 ). Although integrin blocking antibodies had no effects on the NSC pool, EGFR inhibition prevented its expansion in the CCN1-deficient V-SVZ.…”

Neural Stem Cell Niche and Adult Neurogenesis

“…Mature ependymal cells generate a unidirectional CSF flow through oriented cilia beating and formation of gradient guidance cues to promote neuroblasts migration along the RMS (Sawamoto and others 2006). Ependymal cells actively regulate NSC expansion and neuronal fate specification of NCSs through release of Noggin (Lim and others 2000) and ependyma-derived matricellular protein cellular communication network factor 1 (CCN1; Wu and others 2020). Astrocytes derived from SVZ promote proliferation and neuronal fate commitment of NSCs (Gengatharan and others 2016).…”