Dedifferentiation Maintains Melanocyte Stem Cells in a Dynamic Niche
(Updated to add this note: This study is on repigmentation and grey hair research, I realize the title is blind)
Sharing a study looking at repigmentation. That and hair treatments, hair follicle stimulation, and hair follicle microenvironments seem to be a common interest.
Melanocyte stem cells (McSCs) regenerate the pigment producing melanocytes that color hair during each hair cycle. As these stem cells become depleted or stop contributing to hair regeneration, hair gradually loses pigment and turns grey. Understanding why this stem cell population fails has been a long standing question in stem cell biology. The prevailing model proposed that McSCs remain undifferentiated within a specific region of the hair follicle called the bulge, while the cells they produce leave this region, become mature melanocytes, and never return to the stem cell population.
Background info that might help: Stem cells can either maintain their identity or begin differentiating. Differentiation is the process by which a stem cell gradually acquires the structure and function of a specialized cell. In the traditional model, this process moves in one direction. Once a stem cell begins differentiating, it is expected to continue towards becoming a mature cell and permanently lose the ability to function as a stem cell. This study asks whether melanocyte stem cells instead retain the ability to reverse this process.
Back to the paper. The authors found that melanocyte stem cells do not always follow a one way path toward differentiation. During each hair growth cycle, many melanocyte stem cells begin expressing genes associated with mature melanocytes and enter an intermediate stage of differentiation. Rather than continuing directly to become mature pigment producing cells, some later lose these differentiation markers and regain the characteristics and function of melanocyte stem cells. The authors conclude that this revertsal, called differentiation, is a normal mechanism used to maintain the melanocyte stem cell population.
The authors first examined where McSCs are located before hair growth begins. Previous studies suggested that these cells are primarily found in the bulge. However, 3d imaging showed that most McSCs are actually located in the neighboring hair germ. By tracking individual cells over time, the authors showed that McSCs in their hair germ both generated mature melanocytes and produced cells that remained in the stem cell population for future hair cycles. This demonstrated that the hair germ contains the main population responsible for both pigment regeneration and long term maintenance. The authors then ask whether McSCs change ad hair growth begins. They found that these cells changed shape and activated genes involved in pigment production before producing mature melanocytes. Single cell RNA sequencing confirmed that the cells occupied an intermediate molecular state between undifferentiated melanocyte stem cells and fully differentiated melanocytes. These changes occurred early in regeneration, showing that McSCs normally begin the differentiation process during each hair cycle.
To determine whether differentiating cells could return to the stem cell population, the actors permanently labeled McSCs expressing Oca2, a one that is activated late during differentiation. As expected, some of these labeled cells became mature melanocytes that produced pigment in the hair bulb. Unexpectedly, other labeled cells migrated to another region of the hair follicle, switched off pigmentation genes, and persisted as McSCs through multiple rounds of hair regeneration. This demonstrated that cells that had already progressed well into differentiation could reverse that process and regain stem cell function.
The authors showed that nearly all melanocyte stem cells can undergo reversible differentiation rather than maintaining a permanently undifferentiated population. This process is controlled by local signals within the hair follicle. WNT signaling promotes differentiation in the hair germ, whereas reduced WNT signaling in the bulge allows cells to dedifferentiate and regain stem cell function. During aging, many McSCs fail to return to the hair germ and instead remain in the bulge, reducing melanocyte regeneration and contributing to hair greying.
I find it odd that the study doesn't investigate why. Like okay it explains where the cells get stuck... but then doesn't go for more. So like several possibilities could be the cause. The ECM around the follicle stiffens with age, adhesion molecules change, epithelial cells stop producing guidance cues, McSCs themselves lose the migration capacity, or all of these things happen together. It's hard to actually figure out what the best intervention is without that being identified. I'll set aside that a successful repigmentation study does exist and come back to that in the comments so I can just separate ideas. But, restoring McSC movement is something to think about. If those cells are stranded in the bulge and still alive, but just in the wrong place, a treatment that would encourage them to migrate back into the hair germ before the next cycle could be a plan of attack. So manipulating cell adhesion molecules (how tightly cells stick to their surroundings), extracellular proteins, chemokine signaling (cellular communication that guide movement), cytoskeletal regulators (proteins that control the assembly, disassembly, and organization of a cell's structural network) that control migration, etc because these would restore the normal regenerative cycle not trying to force pigment production. The paper shows that McSC identity depends on local signals so another approach could be instead of targeting the stem cells directly, you could try restoring the signals of the aging hair germ (WNT signaling, TGF-β , endothelin, stem cell factor/c-Kit, or notch signaling. Navigating this seems easier said than done though as these pathways regulate many cell types so it would need really precise timing. Also grey hair has been difficult to reverse by changing one of these pathways alone is prob not likely to restore the normal regenerative cycle and this paper kind of reinforces that. Another treatment approach could be if you think about how some McSCs become stuck in a partially differentiated state, it may be possible to push them back toward a differentiated state. The difficult is that forcing cells backwards carries risks if control is lost (abnormal growth or cancer). A different approach to look at would be instead of reversing greying, preserve the normal cycle earlier in life. If the problem is that stem cells gradually lose mobility over decades, then maintaining extracellular matrix structure, preventing fibrosis, or reducing chronic inflammation around the follicle might delay greying. If you are actually interested in these topics and looking through them, these are all 3 common themes we keep seeing across all literature right now in various spaces btw, if you're new here and interested write those down lol. And then a possible treatment could be if you think how McSCs only regenerate pigment during the normal hair cycle, a treatment or therapy might work if it times up with several events. So you'd want to trigger a new hair cycle, restore the proper niche signals, allow stem cells to migrate, and then let pigment producing melanocytes regenerate naturally. But that's very complex.
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Abstract
>For unknow reasons, the melanocyte stem cell (McSC) system fails earlier than other adult stem cell populations, which leads to hair greying in most humans and mice. Current dogma states that McSCs are reserved in an undifferentiated state in the hair follicle niche, physically segregated from differentiated progeny that migrate away following cues of regenerative stimuli. Here we show that most McSCs toggle between transit-amplifying and stem cell states for both self-renewal and generation of mature progeny, a mechanism fundamentally distinct from those of other self-renewing systems. Live imaging and single-cell RNA sequencing revealed that McSCs are mobile, translocating between hair follicle stem cell and transit-amplifying compartments where they reversibly enter distinct differentiation states governed by local microenvironmental cues (for example, WNT). Long-term lineage tracing demonstrated that the McSC system is maintained by reverted McSCs rather than by reserved stem cells inherently exempt from reversible changes. During ageing, there is accumulation of stranded McSCs that do not contribute to the regeneration of melanocyte progeny. These results identify a new model whereby dedifferentiation is integral to homeostatic stem cell maintenance and suggest that modulating McSC mobility may represent a new approach for the prevention of hair greying.
>Supplementary information The online version contains supplementary material available at: https://doi.org/10.1038/s41586-023-05960-6.
>Peer review information Nature thanks Nick Barker, Rui Yi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.