Single-cell transcriptomics reveals lineage trajectory of human scalp hair follicle and informs mechanisms of hair graying

Abstract

Hair conditions, such as hair loss and graying, are prevalent human conditions. But they are often poorly controlled due to our insufficient understanding of human scalp hair follicle (hsHF) in health and disease. Here we describe a comprehensive single-cell RNA-seq (scRNA-seq) analysis on highly purified black and early-stage graying hsHFs. Based on these, a concise single-cell atlas for hsHF and its early graying changes is generated and verified using samples from multiple independent individuals. These data reveal the lineage trajectory of hsHF in unprecedented detail and uncover its multiple unexpected features not found in mouse HFs, including the presence of an innerbulge like compartment in the growing phase, lack of a discrete companion layer, and enrichment of EMT features in HF stem cells (HFSCs). Moreover, we demonstrate that besides melanocyte depletion, early-stage human hair graying is also associated with specific depletion of matrix hair progenitors but not HFSCs. The hair progenitors’ depletion is accompanied by their P53 pathway activation whose pharmaceutical blockade can ameliorate hair graying in mice, enlightening a promising therapeutic avenue for this prevalent hair condition.

Dictys: dynamic gene regulatory network dissects developmental continuum with single-cell multi-omics

“…1b, Methods ). Dictys identified regulation marker TFs distinct from expression markers 56–63 as before ( Fig. 3b, Fig.…”

Biomarkers of aging

“…In early-stage HF aging, HFSCs are maintained but with blunted regeneration responsiveness (Doles et al, 2012;Ge et al, 2020;Giangreco et al, 2008;Keyes et al, 2013;Zhao et al, 2022b). Hair graying is caused by loss of HF melanocytes and their stem cells (Arck et al, 2006;Nishimura et al, 2005), and is also associated with depletion of hair progenitors in human scalp HFs (Wu et al, 2022a). HF aging is also accompanied by changes in the distribution of nearby sensory neurons and atrophy or dysfunction of SGs (Giangreco et al, 2008;Hou et al, 2022).…”

“…In naturally aged IFE, Langerhans cells and their ability to migrate are reduced, the proportion of CD4 + /CD8 + T cells is increased, and the proliferative capacity of monocytes is reduced, accompanied by impaired immune responsiveness and wound healing ability (Keyes et al, 2016;Koguchi-Yoshioka et al, 2021;Nestle et al, 2009). In HF aging, increased immune cell infiltration into HF and activation of inflammatory signaling pathways in HFSCs are observed (Doles et al, 2012;Wu et al, 2022a).…”

“…In aging murine HFs with intact structure, HFSCs displays inflammaging feature mediated by JAK/ STAT activation, along with upregulated NFATC1 expression and downregulated SIRT7 expression, leading to hampered hair cycle activation (Doles et al, 2012;Keyes et al, 2013;Li et al, 2020b). In human scalp HF, activation of P53 and inflammatory pathways are found in HFSCs and hair progenitors at early stage of hair graying (Wu et al, 2022a). Aging HFSCs also upregulate miR-31, which downregulates Clock to activate MAPK/ERK signaling to inhibit hair cycle activation and drive HFSC trans-epidermal elimination (Yu et al, 2021).…”

Single-cell transcriptomics reveals cellular hierarchies and aberrant CTS contraction-mediated premature hair regression in androgenetic alopecia

“…S2E). Based on the expression of SOX9, the above clusters were further identified as 20 different cell types, according to the expression of known lineage markers, including Bulge (KRT15 + , CXCL14 + ), DP (VCAN + , CFD + ), DS (ACTA2 + , CCN2 + ), outer root sheat basal (ORS, KRT14 + , PTHLH + ), ORS suprabasal (ORS SB, KRT17 + ), inner root sheat (KRT6A + ), medulla (KRT85 + , KRT31 + ), proliferating progenitors (PR, MKI67 + ), endothelial cells (Endo, PECAM1 + , VWF + ), immune cells (CD3D + ), Langerhans (CD207 + , CD1A + ), Melanocytes (DCT + , MLANA + ), Vascular smooth muscle cells/pericytes (vSMC, ACTA2 + , RGS5 + , RERGL + ), Sebaceous gland cells (DCD + , SCD + ), sweet gland cells (SwG, KRT8 + , KRT18 + ), interfollicular epidermis spinous (IFE spinous, KRT1 + , KRT10 + ), IFE granular (FLG + , KRT2 + ); cells highly expressing KRT14 but not SOX9 were defined as IFE basal; Inner II (KRT79 + ) is the outer layer of Infundibulum and Isthmus which highly expressed KRT14 and KRT6A in the upper HF region; in contrast, Outer II has a relatively low expression of KRT6A(Cui and Schlessinger, 2015; He et al, 2020; Hughes et al, 2020; Joost et al, 2020; Joost et al, 2018; Joost et al, 2016; Liu et al, 2022; Rahmani et al, 2014; Takahashi et al, 2020; Wu et al, 2022; Yang et al, 2017) (Fig. 1B-D; Supplementary Table 1; Fig.…”