Single cell analysis of transcriptome and open chromatin reveals the dynamics of hair follicle stem cell aging

Abstract

Aging is defined as the functional decline of tissues and organisms, leading to many human conditions, such as cancer, neurodegenerative diseases, and hair loss. Although stem cell exhaustion is widely recognized as a hallmark of aging, our understanding of cell state changes–specifically, the dynamics of the transcriptome and open chromatin landscape, and their relationship with aging–remains incomplete. Here we present a longitudinal, single-cell atlas of the transcriptome and open chromatin landscape for epithelia cells of the skin across various hair cycle stages and ages in mice. Our findings reveal fluctuating hair follicle stem cell (HF-SC) states, some of which are associated with the progression of the hair cycle during aging. Conversely, inner bulge niche cells display a more linear progression, seemingly less affected by the hair cycle. Further analysis of the open chromatin landscape, determined by single-cell Assay for Transposase-Accessible Chromatin (ATAC) sequencing, demonstrates that reduced open chromatin regions in HF-SCs are associated with differentiation, whereas gained open chromatin regions in HF-SCs are linked to the transcriptional control of quiescence. These findings enhance our understanding of the transcriptional dynamics in HF-SC aging and lay the molecular groundwork for investigating and potentially reversing the aging process in future experimental studies.

Hair follicle stem cells promote epidermal regeneration under expanded condition

“…When a certain stem cell activator concentration is reached, some HFSCs will be activated, accompanied by the beginning of the anagen phase ( Ji et al, 2021 ) while the remaining HFSCs still maintained quiescence. Activated HFSCs play a role in hair growth and tissue regeneration, exhibiting versatility in response to various external stimuli ( Zhang et al, 2023 ; Shwartz et al, 2020 ). Studies have highlighted the significance of the microenvironment, especially the role of local mechanics in tissue engineering and regeneration.…”

“…A transcriptomic study on expanded mouse skin reported that epidermal cells serve as crucial effector cells in skin expansion, with epidermal cell proliferation and renewal playing a decisive role in skin regeneration ( Joost et al, 2018 ; Aragona et al, 2020 ). It was observed that expansion upregulates a number of HFSC-associated genes and the possible downstream differentiated cells—epidermal stem cells, including Krt14, Krt24, Cd34, Krt79, Fgf18, Lgr6, and Lgr5 ( Zhang et al, 2023 ; Zhao et al, 2023 ). The epidermal basal cells of keratinocytes comprise epidermal stem cells that express Krt14 as a marker of actively proliferating keratinocytes ( Wiśniewska et al, 2021 ).…”

“…The Shh pathway primarily controls signal transduction in the epidermis and can respond to mechanical loading of different tissues and stages both in vitro and in vivo ( Zhang et al, 2023 ). HFSCs, perpetually immersed in a mechanically dynamic niche, are linked to Shh pathway activity ( Huang et al, 2016 ).…”

“…Shh signaling not only enhances both epidermal and HF growth, but preserves the stemness of HFSCs ( Suen et al, 2020 ). Classic HH signal pathway transduction usually involves several key elements, including the HH ligand, cell surface receptor patched (PTCH), membrane protein smoothened (SMO), transcription factor glioma (GLI), and suppressor of fused protein ( Zhang et al, 2023 ). Among the HH pathway, the Shh pathway, which is currently being extensively investigated, is essential in HFs ( Ma et al, 2017 ).…”

Determinants of Chromatin Organization in Aging and Cancer—Emerging Opportunities for Epigenetic Therapies and AI Technology

“…Stem cell fate regulation is complex and controlled by a combination of extracellular signals, transcriptional programs and chromatin organization [ 78 , 79 ]. In stem cells, chromatin is generally maintained in a more open and relaxed state, which facilitates the expression of genes necessary for maintaining pluripotency and cellular quiescence, while compaction of the chromatin is associated with differentiation [ 80 , 81 ].…”