SIRT 7 activates quiescent hair follicle stem cells to ensure hair growth in mice

Abstract

Hair follicle stem cells (HFSCs) are maintained in a quiescent state until activated to grow, but the mechanisms that reactivate the quiescent HFSC reservoir are unclear. Here, we find that loss of Sirt7 in mice impedes hair follicle life‐cycle transition from telogen to anagen phase, resulting in delay of hair growth. Conversely, Sirt7 overexpression during telogen phase facilitated HSFC anagen entry and accelerated hair growth. Mechanistically, Sirt7 is upregulated in HFSCs during the telogen‐to‐anagen transition, and HFSC‐specific Sirt7 knockout mice (Sirt7f/f;K15‐Cre) exhibit a similar hair growth delay. At the molecular level, Sirt7 interacts with and deacetylates the transcriptional regulator Nfatc1 at K612, causing PA28γ‐dependent proteasomal degradation to terminate Nfatc1‐mediated telogen quiescence and boost anagen entry. Cyclosporin A, a potent calcineurin inhibitor, suppresses nuclear retention of Nfatc1, abrogates hair follicle cycle delay, and promotes hair growth in Sirt7−/− mice. Furthermore, Sirt7 is downregulated in aged HFSCs, and exogenous Sirt7 overexpression promotes hair growth in aged animals. These data reveal that Sirt7 activates HFSCs by destabilizing Nfatc1 to ensure hair follicle cycle initiation.

Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications

“…, HSCs and muscle SCs (MuSCs)) via rejuvenating aged quiescent SCs controlled by various autophagy pathways such as the p38/mitogen-activated protein kinase (MAPK) signaling pathway[ 176 , 177 ]. Uncovering the autophagy mechanisms underlying SC quiescence presents novel therapeutic strategies to release the cells out of the quiescent state, promoting their proliferation and differentiation (such as induced activation of quiescent NSCs for neuron injury), or re-establishing quiescence to prevent aberrant proliferation and differentiation or premature senescence (such as anti-cancer therapeutics), which carry the risk of cancer SCs (CSCs)[ 178 , 179 ]. These stressors ( e.g.…”

The Role of the Immune Response in the Development of Medication-Related Osteonecrosis of the Jaw

“…Moreover, BPs were confirmed to inhibit RANKL-induced osteoclast differentiation by the suppression of the nuclear factor of activated T-cells c1 (NFATc1) ( 104 ). As a transcription factor of the nuclear factor in the activated T cell (NFAT) family ( 105 ), NFATc1 is a vital downstream target of RANK. When RANKL binds to RANK, TNF receptor-associated factor 6 (Traf6) is recruited and activated, thereby causing signal pathway activation of NF-κB, MAPK, and c-Fos ( 106 ).…”

Stem cell‐intrinsic mechanisms regulating adult hair follicle homeostasis

“…Intriguingly, increasing Sirt7 expression in aged HFs can alleviate ageing-related HF growth defects. 86 Thus, Sirt7 may be useful as a potential therapeutic target for hair loss due to ageing.…”

“…Further in vitro experiments revealed Sirt7 mediated degradation of Nfatc1, a HFSC quiescence TF, as one of the mechanisms behind proper telogen‐anagen transition. Intriguingly, increasing Sirt7 expression in aged HFs can alleviate ageing‐related HF growth defects 86 . Thus, Sirt7 may be useful as a potential therapeutic target for hair loss due to ageing.…”

“…Sirt7 is a deacetylase commonly associated with ribosomal RNA transcription and cell senescence, 85 and its expression in the bulge is necessary for timely anagen progression. 86 Upon Sirt7 loss, HFSC activation and HF growth were delayed, while inducing Sirt7 expression during telogen led to significantly earlier anagen entry. Further in vitro experiments revealed Sirt7 mediated degradation of Nfatc1, a HFSC quiescence TF, as one of the mechanisms behind proper telogen-anagen transition.…”