Regulatory T cells interact with skin cells using glucocorticoid hormones to generate new hair follicles and promote hair growth


Salk scientists have uncovered an unexpected molecular target of a common treatment for alopecia, a condition in which a person’s immune system attacks their own hair follicles, causing hair loss.

The findings, published in Nature Immunology on June 23, 2022, describe how immune cells called regulatory T cells interact with skin cells using a hormone as a messenger to generate new hair follicles and hair growth.

“For the longest time, regulatory T cells have been studied for how they decrease excessive immune reactions in autoimmune diseases,” says corresponding author Ye Zheng, associate professor in Salk’s NOMIS Center for Immunobiology and Microbial Pathogenesis.

“Now we’ve identified the upstream hormonal signal and downstream growth factor that actually promote hair growth and regeneration completely separate from suppressing immune response.”

The scientists didn’t begin by studying hair loss. They were interested in researching the roles of regulatory T cells and glucocorticoid hormones in autoimmune diseases.

(Glucocorticoid hormones are cholesterol-derived steroid hormones produced by the adrenal gland and other tissues.) They first investigated how these immune components functioned in multiple sclerosis, Crohn’s disease and asthma.

They found that glucocorticoids and regulatory T cells did not function together to play a significant role in any of these conditions. So, they thought they’d have more luck looking at environments where regulatory T cells expressed particularly high levels of glucocorticoid receptors (which respond to glucocorticoid hormones), such as in skin tissue.

The scientists induced hair loss in normal mice and mice lacking glucocorticoid receptors in their regulatory T cells.

“After two weeks, we saw a noticeable difference between the mice – the normal mice grew back their hair, but the mice without glucocorticoid receptors barely could,” says first author Zhi Liu, a postdoctoral fellow in the Zheng lab.

“It was very striking, and it showed us the right direction for moving forward.”

The findings suggested that some sort of communication must be occurring between regulatory T cells and hair follicle stem cells to allow for hair regeneration.

Using a variety of techniques for monitoring multicellular communication, the scientists then investigated how the regulatory T cells and glucocorticoid receptors behaved in skin tissue samples.

They found that glucocorticoids instruct the regulatory T cells to activate hair follicle stem cells, which leads to hair growth.

This crosstalk between the T cells and the stem cells depends on a mechanism whereby glucocorticoid receptors induce production of the protein TGF-beta3, all within the regulatory T cells.

TGF-beta3 then activates the hair follicle stem cells to differentiate into new hair follicles, promoting hair growth. Additional analysis confirmed that this pathway was completely independent of regulatory T cells’ ability to maintain immune balance.

However, regulatory T cells don’t normally produce TGF-beta3, as they did here. When the scientists scanned databases, they found that this phenomenon occurs in injured muscle and heart tissue, similar to how hair removal simulated a skin tissue injury in this study.

“In acute cases of alopecia, immune cells attack the skin tissue, causing hair loss. The usual remedy is to use glucocorticoids to inhibit the immune reaction in the skin, so they don’t keep attacking the hair follicles,” says Zheng. “Applying glucocorticoids has the double benefit of triggering the regulatory T cells in the skin to produce TGF-beta3, stimulating the activation of the hair follicle stem cells.”

This study revealed that regulatory T cells and glucocorticoid hormones are not just immunosuppressants but also have a regenerative function. Next, the scientists will look at other injury models and isolate regulatory T cells from injured tissues to monitor increased levels of TGF-beta3 and other growth factors.

Hair follicles (HFs) consist of the infundibulum, isthmus, and hair bulb. The hair bulb is located in the thickened base of the hair root and consists of an epithelium-derived matrix wrapped around a mesenchymal cell-derived dermal papilla (DP), which contains DP cells, endothelial vascular cells, and extracellular matrix (ECM). Cell–cell contacts, cell–matrix interactions, and tissue–neural interplay are all controlled by epithelial–mesenchymal interactions (EMIs), which also incorporate morphogens, cell adhesion factors (proteoglycans, etc.), growth factors, ECM molecules, hormones, cytokines, enzymes, and specific pharmacologically relevant molecules (retinoid, etc.) and their receptors (1).

Sonic hedgehog (SHH), wingless (Wnt), bone morphogenetic protein (BMP), fibroblast growth factor (FGF), their receptors, and other pathways are linked to embryonic HF development, the hair cycle, and skin wound healing (2). Other underlying molecular families associated with HF morphogenesis are the transforming growth factor-beta (TGF-β) family and neurotrophic proteins (3, 4). In HFs, DPs can secrete components that act on the peripheral matrix, such as epidermal growth factor (EGF), FGF, hepatocyte growth factor (HGF), insulin-like growth factor-I (IGF-I), keratinocyte growth factor (KGF or FGF-7), TGF-β, basic FGF (bFGF or FGF-2), and interleukins (IL-1, etc.) (5). DP ensures and regulates the hair growth and hair cycle in order.

Through EMI between DPs and epithelial cells, HFs participate in postinjury skin wound healing. In patients with extensive skin burns, transplanting HF progenitor cells enhances angiogenesis, regulates the inflammatory response, speeds wound healing, and improves the physiological function of skin regeneration. HF progenitor cell transplantation is an innovative technique and could be a new therapeutic option for long-term unhealed wounds (6).

EMI in HF Morphogenesis and Cyclic Regeneration
HF Morphogenesis

Hair follicle morphogenesis is the climax of a series of EMI through coordinated epidermal–mesenchymal signaling and gradual tissue remodeling, with stem cell populations evolving into a complete HF structure (7, 8). Due to the availability of mouse specimens, mouse models play a key role in EMI research during HF morphogenesis and cycle (9). Initially, the dermis emits the first dermal signal, which stimulates the production of epidermal placodes. The placode is the initial hair structure, a concavity of the epidermis descending into the dermis. Subsequently, the placode delivers epidermal impulses to the dermal cells beneath the epidermis, leading to the formation of dermal condensate (DC) (7, 8). Following the DC’s second dermal signal, proliferative epithelial cells shape pegs and downwards (Figure 1A). HF stem cells (HFSCs) stimulate the subsequent downward expansion of hair pegs, eventually forming an integral HF.

Figure 1. The morphogenesis and cycling of the hair follicle. (A) As the earliest and paramount signal in the first hair wave, Wnt induces placode and dermal condensate formation and intrigues complex inter-signal dynamics. (B) In mature hair follicles, stem cells at different sites can be characterized by specific markers. (C) EMI interaction occurs between DP, hair germ and its progeny, and hair matrix, during hair anagen initiation. The green color in the figure represents DP signals that initiate the anagen, the red color inhibits the hair follicle cycle, and the gray color represents the matrix signals. BMP and FGF18 suppress hair stem cells, whereas Wnt and FGF7/10 activate them. CTGF, connective tissue growth factor; Eda, ectodysplasin A; Edar, ectodysplasin A receptor; DKK, Dickkopf; Gli1, GLI family zinc finger 1; Lef1, lymphoid enhancer-binding factor 1; Lgr, leucine-rich repeat-containing G-protein coupled receptor; Lhx2, LIM homeobox 2; Lrig1, leucine-rich repeats and immunoglobulin-like domains protein 1.

HF Cyclic Regeneration
Bulge HFSCs and mesenchymal DPs act as progenitor cells for the HF epidermal and dermal layers, respectively (7). In the late telogen phase of humans and mice, DP activates bulge HFSCs, creating germ cells that continue to build the hair matrix, resulting in the production of the inner root sheath and the hair sheath (10).

Dermal papilla numbers are stable during HF cycles but drastically decrease in patients with androgenetic alopecia (11). Maintenance of the quantity and function of DP cells is required for healthy hair. In normal conditions, HF dermal stem cell (hfDSC) progeny supply lower DP cells and diverge toward the dermal sheath, but with injury, cell loss, senescence, and HF hypertrophy, they are transported to the upper DP, which initiates significant HF regeneration (12). During the anagen phase, hfDSCs replenish the DP and dermal sheath and exit the DP into the dermal cup during the catagen phase. Then, they enter a quiescent state or undergo apoptosis. Accordingly, to maintain the HF cycle, a balance between hfDSC reduction (differentiation and withdrawal from the hfDSC niche) and increase is critical (13).

The dermal papilla is dependent on EMI to induce HF regeneration, and the function of DP is inextricably tied to the progenitors of the epithelial matrix that surrounds it (14). The hair matrix is located in the proliferative zone of the hair bulb and consists of epithelial stem cells and transient amplifying cells. DP awakens the transient amplifying cells in anagen, enabling hair germs to migrate down with the DP, similar to how epithelial stem cells behave during embryonic HF development (Figure 1C) (8). In late anagen and catagen, DP loses contact with the hair matrix and ascends below the lower bulge as the hair sheath shortens. Moreover, the hair matrix transforms into secondary hair germs. In the next cycle, the secondary hair germ encloses the DP to form the newly generated hair matrix (15, 16).

Growth Factors

Epidermal growth factor influences the lungs, mammary glands, small sweat glands, and skin, which is expressed in the HF outer root sheath and differentiated sebaceous glands (10). The EGF family impedes HF morphogenesis, generally manifesting as placode and DC deficits (7). The EGF family also controls hair sheath differentiation and morphology, with TGF-α mutations and deletions producing wavy hairs owing to distortions in the outer and inner root sheaths (2, 8).

The fibroblast growth factor is located in the epidermis and DC and is involved in placode formation in most circumstances. Similar to embryonic development, FGFR2b ablation results in abnormalities in the granular layer and skin appendages (2, 35, 36). In signal networks, FGF20 is secreted after Wnt signaling activation in epithelial placodes and promotes DC formation (37). Identifying the function of the FGF family is important due to the various mechanisms that they modulate in the hair cycle and related disorders. FGF5/18, as catagen-promoting factors, can inhibit stem cell growth, accelerating the anagen–catagen transition and adjusting the hair sheath length (3, 15, 38, 39). Similar to FGF7/10, more FGFs operate as transient amplifying cell-activating signals, catalyzing the telogen–anagen transition and HF renewal (8).

Transforming growth factor-beta has anti-proliferation potential for most epithelial cells, including follicular keratinocytes. When HF enters catagen, the epithelial TGF-β/activin signal induces apoptosis (3, 8, 38, 40). As a typical human hair disease-related gene, TGF-β deletion in HFSCs impairs the differentiation of adjacent pigmented stem cells in human follicular keratinocyte cells (41, 42).

Platelet-derived growth factor (PDGF) regulates cell growth and mesenchymal cell division, which remains the first epithelial signal in the placode (43). As a downstream target of SHH, PDGF is secreted by the epidermis, with receptors in the dermal sheath and DP, functioning in an adipose-stimulating manner to enhance HF regeneration (8). In addition, PDGF is secreted by the HF matrix during anagen and has a facilitative effect on the hair germ (8, 44).

Secreted by DP, vascular endothelial growth factor (VEGF) stimulates the expression of VEGFR-2 in human epidermal cells, hence promoting their proliferation, differentiation, and migration (45). Interestingly, VEGF can directly act on DP and promote human HF growth by stimulating local blood vessels during anagen, with bFGF promoting VEGF angiogenesis (8, 46, 47).

reference link :

Original Research: Closed access.
Glucocorticoid signaling and regulatory T cells collaborate to maintain the hair follicle stem cell niche” by Ye Zheng et al. Nature Immunology


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