Hair loss is caused by stem cells that lose glue and escape the hair follicle

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A newly discovered cause of balding in aging male mice could reveal a cause of hair loss in men and women as well, reports a study from Northwestern Medicine scientists. The findings provide new insight into how hair and tissues age.

The study, published in Nature Aging in October, shows as hair stem cells age, they lose the stickiness that keeps them lodged inside the hair follicle. As their adhesiveness wanes, the stem cells escape from their location, called the bulge, into the dermis. Outside their delicate microenvironment, they generally can’t survive.

“The result is fewer and fewer stem cells in the hair follicle to produce hair,” said lead author Rui Yi, the Paul E. Steiner Research Professor of Pathology at Northwestern University Feinberg School of Medicine. “This results in thinning hair and ultimately baldness during aging.”

The finding could likely apply to older men and women with thinning hair because there are many similarities between mice and humans in hair and stem cells, Yi said.

This is the first time hair follicle aging has been tracked in live animals, allowing scientists a real-time cellular view of the aging process.

Scientists also discovered two key genes responsible for enhancing adhesiveness of the stem cells. In a current study, they are trying to reinstate these genes to see if that will reverse hair loss.

It’s always life and death for hair follicles

Our hair follicle goes through cycles of life and death. During these normal cycles, a large number of stem cells stay permanently lodged in the stem cell compartment of hair follicles to keep producing hair follicle cells. In this study, scientists discovered what happens to these stem cells due to aging, resulting in thinning hair and balding.

How the study advances research

“We believe this stem cell escape mechanism has never been reported before, because nobody could track the aging process in live animals,” Yi said.

Scientists knew hair follicles become miniaturized during aging. But how it happened wasn’t clear. Many scientists thought it was due to cell death or the inability of cells to divide as they age.

“We discovered, at least in part, it is due to hair follicle stem cells migrating away from their niche,” Yi said. “Cell death also occurs during our observation. So, our discovery doesn’t dispute existing theories but provides a new mechanism.”

How the study worked

Scientists labeled hair follicle cells, including stem cells, with green fluorescent protein in live mice and used a long, wavelength laser to observe hair follicle cells during aging. They observed the same hair follicle repeatedly for many days (in one case, they observed one hair follicle for 26 days and saw the entire process of hair follicle degradation). They saw signs of unusual cell escape.

Next, they compared gene expression levels between young and old animals in follicle stem cells. They found less expression of genes responsible for adhesion in old hair follicle stem cells.

Researchers then identified a special group of genes which may regulate these cell adhesion genes. They genetically knocked out these two genes, FOXC1 and NFATC1, in mutant animals. The result: rapid progress of hair loss starting at four months. Within 12 to 16 months, these mice became completely bald. Finally, researchers used the live imaging to observe stem cell escape in these mutant mice and captured the action of stem cells migrating away from stem cell niche.

Other Northwestern authors are Chi Zhang (a visiting student), Dongmei Wang, Jingjing Wang and Dr. Tsutomu Kume.


Four-hour time-lapse video shows the escape of stem cells, marked by arrows, from a hair follicle in an aging mouse. Some cells (red and green arrows) change the shape of their nuclei and squeeze through what are likely small openings in the follicle membrane before migrating away separately. Zhang et al, Nature Aging

Adult stem cells (SCs) undergo long-term self-renewal and multilineage differentiation (1, 2) and are responsible for maintaining tissue homeostasis and repairing wounds. Irrespective of usage frequency, SCs endure increasingly strained demands to maintain tissue integrity over the course of a lifetime of repeated environmental insults. Initially viewed as the long-sought fountain of youth, SCs in aging tissues do not have an endless functional output, and inevitably tissue fitness wanes (3⇓⇓⇓⇓⇓⇓⇓–11).

What accounts for this age-related decline in SC activity remains unclear. Increasing evidence from young adult tissues points to the importance of the SC niche (i.e., its tissue microenvironment) as a key modulator of SC behavior. Thus, in order to identify the drivers of aging, and devise interventions that prolong adult SC function and improve age-related tissue fitness, it will be necessary to interrogate not only the aging SCs, but also their niche.

Murine skin represents an excellent model to tackle this important problem. During embryogenesis, skin epithelium begins as a single layer of unspecified progenitors, which progressively give rise to the stratified layers of the epidermis and its appendages, including hair follicles (HFs), sebaceous, sweat, and mammary glands. As morphogenesis proceeds, SCs and progenitors are set aside in discrete niches, each of which then instructs their residents what to do and when (12⇓⇓⇓–16).

In adult skin, HFSCs reside in an anatomical niche called the bulge (17), where they fuel the synchronized, cyclical bouts of quiescence (telogen), active hair growth (anagen), and destruction (catagen). Just above the bulge is the attachment site of the arrector pili muscle (APM), which thermoregulates by controlling the positioning of the hairs relative to the body surface. Also located above the bulge are four different types of sensory neurons that enable perception of touching or stroking of the hair coat.

During the quiescent period, the dermal papilla (DP) resides directly below the bulge. Prolonged cross-talk between the DP and adjacent HFSCs is needed to enter the hair growth phase. Additional inputs from the lymphatic capillaries, adipose tissue, dermal fibroblasts, immune cells (e.g., macrophages and regulatory T cells), and HFSC progeny themselves have all been reported to impact HFSC behavior, and participate in the transition from resting state to active HF regeneration and hair growth (18⇓⇓⇓⇓⇓⇓⇓⇓⇓⇓–29). The lymphatic network also integrates the activity of HFSCs across the tissue (28).

In normal homeostasis of young mice, each new hair cycle begins when positive signals from various niche inputs override inhibitory cues, prompting HFSCs to regenerate the lower two-thirds of the HF and grow hair. In response to a partial-thickness wound, HFSCs are also mobilized to re-epithelialize the missing tissue in the interfollicular epidermis and in the upper HF, including the sebaceous glands (19, 30⇓⇓⇓⇓⇓⇓⇓–38).

In transit, they adopt certain features of the stem cells of these new tissues, while retaining characteristics of the HFSCs, a phenomenon that we’ve referred to as “lineage infidelity” (35). Once the wound is healed, however, this transient state is resolved, and HFSCs take on the identity characteristic of the destination-resident SCs whose niches they have now adopted.

Such broadening of lineage choices is similarly observed when HFSCs are taken from their native niche and engrafted into foreign hosts in transplantation studies (39, 40). Together, these findings illustrate the impact of the niche on SC behavior in homeostasis and wound healing.

Less clear is how changes in the niche impact SC activity and lineage choices in the skin later in life. Age-related declines in SC activity and tissue fitness have been described for both epidermis (41⇓–43) and HFs (44⇓⇓⇓–48), and in many cases, the role of aging tissue microenvironment has been implicated (24, 41, 42, 44, 46, 47, 49, 50).

The relation between changes in the aging niche and lineage choices of the SCs remains unclear. Curiously, age-related skewing of SC lineage choices or precocious differentiation has been noted in other tissues (51⇓⇓–54). In this regard, aging HFSCs have been suggested to undergo epidermal conversion, thereby accounting for the age-related miniaturization of HFs and paucity of hairs (48).

In contrast to wound repair, however, where young HFSCs undergo fate switching upon taking up a new niche residence (35), an age-related switch in SC fate within their native niche would imply that either there is an intrinsic fate plasticity in SCs that becomes unstable with age, or that the niche has been modified in an age-related manner to promote such skewing of fates.

In the present study, we sought to explore these possibilities by characterizing the multifaceted phenotypic and molecular changes that take place in aged HFSCs and their surrounding tissue microenvironment. Unexpectedly, we discovered that HFSCs within their aged niche maintain lineage identity, and show little evidence of epidermal conversion.

While remaining faithful in their lineage identity, aged HFSCs displayed clear changes in the expression of extracellular matrix (ECM) genes, and these perturbations were accompanied by distinct structural alterations within the bulge niche. Also notable were marked age-related changes in the nonepithelial components of the dermal microenvironment that are known to impact HFSC behavior.

Correspondingly, we found that aging skin is severely compromised in its ability to regenerate HFs following an injury, a feature that relies not only upon SC function, but also contributions from the surrounding dermis. Finally, we show that these extrinsic stimuli largely override the intrinsic differences displayed by young and aged HFSCs. Thus, neonatal dermal cells rejuvenate aged HFSCs during in vivo transplantations, while aged dermal cells fail to support even young HFSCs under such circumstances. Overall, our findings point to the importance of the tissue microenvironment as a key functional determinant of SC aging.

reference link : https://www.pnas.org/content/117/10/5339


More information: Chi Zhang et al, Escape of hair follicle stem cells causes stem cell exhaustion during aging, Nature Aging (2021). DOI: 10.1038/s43587-021-00103-w

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