New Understandings of Hair Follicle Stem Cell Populations and Their Role in Growth [2025]

The Classic Model: "Bulge" HFSCs Drive Hair Cycles

For decades, the outer root sheath (ORS) bulge region of the follicle has been viewed as the primary reservoir of hair follicle stem cells (HFSCs). Cells in this niche are slow-cycling and multipotent. They maintain themselves and regenerate the hair shaft lineage through each anagen-catagen-telogen cycle. This is the basis of our traditional understanding of hair biology and regeneration.

A Paradigm Shift: Discovery of Upper and Middle Follicle Stem Cells

A Transformative 2025 Report from the University of Virginia

On February 19, 2025, researchers led by Lu Q. Le, MD, PhD at UVA reported a previously under-appreciated population of HFSCs residing in the upper and mid regions of the follicle, higher up than the classic bulge. When selectively depleted in mice, these cells caused hair growth to stop altogether. Intriguingly, the research team found that these cells are still preserved in human bald scalps, even when all hair shafts have vanished.

Key insights

1. These upper/middle HFSCs act as early "ancestor" cells for the bulge niche itself
2. The bulge is derived downstream from this population, not upstream as previously assumed.
3. Therefore, bulge-centric therapies risk missing a root source of regenerative capacity.

The findings, soon to be published in the Journal of Clinical Investigation, herald a major shift: hair growth might be sustained or restored by reactivating these dormant progenitors, not just the bulge HFSCs.

Biological Relevance: Features of the Novel HFSCs

1. Anatomical Position and Cycling Behaviour

These cells are scattered along the upper and middle ORS—positions formerly considered transit-amplifying zones. Lineage tracing shows they are:

• Slow-cycling, lick classical SCs.
• Survive catagen, unlike many lower ORS cells.
• Actively differentiate into the bulge, replenishing the traditional niche.

2. Functional Proof via Ablation

In the UVA mouse model, genetic ablation of these stem cells temporarily halted anagen initiation. Conversely, preservation of the bulge without these upstream cells did not rescue hair growth, a demonstration of hierarchical importance.

3. Persistence in Human Bald Scalp

Scalp biopsies from elderly or pattern bald individuals showed that while the bulge might shrink or become inactive, these upstream stem cells often remain intact. This suggests hair loss may often be dormancy, not destruction, of progenitor reservoirs.

Therapeutic Implications: Reactivating the Dormant Reservoir

A New Strategy for Regenerative Medicine

• Activation-based therapy: small molecules, biologics, or light protocols aimed at reawakening the dormant population and guiding them to repopulate the bulge.
• Cell-based therapy: ex vivo expansion and transplantation of upper-or‑mid follicle HFSCs to bald regions.
• Gene-targeted signalling: modulating pathways (e.g. Wnt/β‑catenin, FGF, sonic hedgehog) upstream in the follicle to bias differentiation toward follicle growth.

Why This Moves Beyond Current Treatments

• Minoxidil and finasteride indirectly affect HFSC status and vascular dynamics, but do not selectively energise dormant stem cells.
• Stem cell or exosome injections into bald skin have shown limited or transient benefit; targeting remaining resident stem cells may prove more sustainable.

This discovery opens the door for new stem cell activation therapies and reinforces the value of supporting the scalp environment with clinically active ingredients. While research into activating these cells continues, scalp care regimens that maintain follicular health may help create the ideal microenvironment for reactivation.

If you're looking to support scalp health with evidence-informed care, you may consider the following:

• BioScalp DHTI Control Kit: A 3-step system formulated to reduce DHT buildup, soothe inflammation, and support follicle function.
• BioScalp DHTI Control Shampoo: A daily shampoo with key actives designed to reduce scalp oil and help maintain follicular balance.

These products won’t directly activate stem cells, but they may help support the scalp environment that encourages stem cell reawakening, especially when combined with future therapeutics based on these UVA findings.

Broader Context: The HFSC Niche and the Role of Cholesterol

Sympathetic neurons as messengers

Recent work has revealed that cholesterol supplementation can stimulate hair growth, not by topical "nutrition", but via a neuroendocrine mechanism:

• Subcutaneous cholesterol activates the PKA signalling cascade, leading to phosphorylation of tyrosine hydroxylase at Ser‑40.
• This augments sympathetic nerve activity locally in the follicle and increases HFSC proliferation.
• Ablation of sympathetic nerves removes the beneficial effect of cholesterol, demonstrating that nerve signals can gate HFSC activation.

In short, cholesterol’s impact arises through stimulating nerve-dependent HFSC engagement, illustrating one way systemic metabolism intersects with follicle biology.

Linking the dots

These findings dovetail with past work on the hair follicle niche:

• Sympathetic nerves wrap closely around the arrector pili and the follicular epithelial stem cell region.
• They release norepinephrine, acting directly on HFSCs to regulate quiescence vs. activation.
  
• Cholesterol transporters fluctuate during the hair cycle, pointing to the importance of local lipid homeostasis in SC niche dynamics, possibly including substrate availability for signalling cascades.

This network suggests that metabolic cues and nerve signals may converge on the upper/mid HFSC reservoir to control the transition between growth and dormancy.

Challenges Ahead & Future Research Directions

Conclusion

The 2025 UVA report identifying an ancestral stem cell source above the classic HF bulge has introduced a sea change in hair regeneration science. Rather than treating pattern baldness as a bulge-localised issue, we now recognise:

• Hair growth, and possibly hair regrowth, depends on upstream progenitors.
• These skeletal cells, still present in many bald scalps, may be reactivated pharmacologically or via niche modulation.
• Lifestyle or metabolic signals (e.g. cholesterol) that modulate systemic or nervous regulation might leverage this latent potential.
• This multifactorial insight unites previously separate threads: HF stem cell biology, sympathetic nerve regulation, lipid homeostasis, and injury-responsive microenvironment engineering.

Together, these findings mark a turning point: hair regeneration may shift from a bulge restoration paradigm to a model of reactivating the “ancestor” governor population above the bulge, opening creative pathways for therapies that restore natural follicles, structure, and function.

As the field moves toward therapies that reactivate this dormant population, maintaining a clean, nourished, and balanced scalp environment could become even more important. Brands like BioScalp offer products that align with this science-forward, follicle-supportive approach.