Hair Loss and MicroRNA 22

A fair number of research groups are involved in investigations of the fine details of age-related hair loss. As in most research related to aging, scientists are for the most part much more interested in mapping the chain of change and consequence in cellular biochemistry than in seeking out first causes. The outcome here is that later attempts to build therapies based on new knowledge tend to involve prevention or alteration of downstream consequences of cellular and molecular damage rather than trying to repair or prevent that damage. All other things being equal, this is never going to be the best path forward. For one the consequences of a given form of damage will always be more numerous and more complex than the damage itself: much more effort is involved in chasing down all the loose ends. Secondly messing with the consequences of damage does nothing about the damage itself, which remains to continue causing harm.

During the active phase of the hair growth cycle, stem cell activity sustains an actively dividing population of epithelial cells at the base of the hair follicle called matrix cells. As progeny of the matrix cells move upward from the follicle base (or bulb), they differentiate into a hardened hair shaft, which emerges above the skin surface. Fully differentiated hair shafts consist of dead, but mechanically sound and highly cross-linked, keratin-filled cells. After a period of active hair shaft production, follicles activate an involution program, during which a large portion of epithelial cells die, and the remaining stem cells are reduced to a tight cluster underneath the skin surface. These follicles then remain dormant for some time; however, they can undergo activation and restart active hair shaft production.

The growth, regression, and resting phases together constitute the hair growth cycle, and this cycling can be influenced by a variety of local and systemic signaling factors. Consequently defects in hair cycling can arise from changes in the normal signaling milieu due to disease, aging, or injury. Commonly, in humans, scalp hair follicles enter resting phase prematurely, and hairs shafts become shorter and fall out, resulting in visible baldness. Therefore, identifying new signaling regulators of hair follicle regression will provide a better understanding of the hair loss pathogenesis mechanism and will likely identify novel therapeutic targets.

To test the function of miR-22, we generated a genetic tool to induce miR-22 overexpression in mouse hair follicles, and interestingly, found that increasing miR-22 results in hair loss in mice due to the premature regression of actively growing follicles. Surprisingly, our data reveal that the expression of over 50 distinct keratin genes are markedly reduced by miR-22 and that silencing of keratin-mediated hair shaft assembly by miR-22 is a prerequisite for follicle regression. In the future, our findings are likely to benefit human hair loss research efforts. Androgenic alopecia, where premature regression of scalp hair follicles is induced by increasing androgen levels, is the most common hair loss disorder in humans. Our unpublished data show that two binding sites for an androgen receptor are located in the promoter of both human and mouse miR-22. These findings support the hypothesis that miR-22 functions in the pathogenesis of Androgenic Alopecia, warranting future studies of miR-22 inhibitors as potential anti-hair loss drugs.

Link: http://blogs.plos.org/biologue/2015/06/16/understanding-images-micrornas-contribute-to-hair-loss-and-follicle-regression/

Comments

As always I appreciate the clarity of thought and writing. Going after the symtoms of aging one by one and at the level they're occuring rather than at the root level is wrongheaded at best. As for hair loss, and maybe the answer is hidden somewhere in that dense quote, which type of root damage is responsible? Intracellular junk?

Posted by: Northus at June 17th, 2015 9:29 AM

@Northus: For hair loss, I'm not sure as to the root damage. All of the research I know of is starting at a level above that, such as stem cell dysfunction or rising levels of oxidative stress. Which is fair enough: no-one yet has a clear and defensible chain of consequences mapped out starting from the SENS-outlined forms of fundamental damage that leads to stem cell dysfunction, for example.

The whole point of the SENS approach is to bypass all of the work needed for that complete map in favor of a quicker rush to therapies based on damage repair, and prove effectiveness by doing it rather than analysis of mechanisms up front, since that's expensive and slow and time counts.

Posted by: Reason at June 17th, 2015 9:46 AM

"The whole point of the SENS approach is to bypass all of the work needed for that complete map in favor of a quicker rush to therapies based on damage repair, and prove effectiveness by doing it rather than analysis of mechanisms up front, since that's expensive and slow and time counts.”

Mice and other animal models have age-related hair loss.

If SENS could partially and temporarily reverse that, even if it did not elucidate the mechanism, then it would go a long way toward “proving SENS”.

What isn’t such a proof of concept pursued on the short term (e.g., reverse age-related hair loss in mice within 5 years)?

Posted by: Daniel Lemire at June 17th, 2015 11:28 AM

Reason, yes it makes sense to not spend too much time and effort creating a map of all the causal links, and instead focus on repairing the root damage and then let the symtoms of aging sort themselves out, so to speak. But we nonetheless do in some cases know that link, including for Alzheimers and Atherosclerosis and even wrinkles, and I've found it helpful both for my own general understanding and for advocacy to know these links whenever it's possible. For example, people often find it interesting that it's the same root damage that causes wrinkles and hypertension (and atherosclerosis). That may be a simplification, but AGEs play a part in both, and saying that helps get the idea across that the deadly diseases of aging and the normal and "harmless" signs of aging like wrinkes are the SAME THING at the root level, only differing in degree and location etc. Which is helpful since it points to aging itself as being the problem and not "the diseases of aging", plus people really enjoy the idea that you really can cure something like wrinkles at the root level, which is often news to them (while they do know about efforts to cure the diseases of aging).

Posted by: Northus at June 17th, 2015 10:19 PM

Hi Daniel,

A few things on that ... First and foremost, there are already a fair number of people working on a perfectly SENSible approach to this problem, namely cell therapy for hair loss. Early research mostly focused on transplanting hair follicles directly, but the most promising approach currently seems to be dermal papilla cells, which activate resident epithelial progenitor cells and regulate the formation, regeneration, and growth cycle of hair follicles. Indeed, earlier this year, researchers at the Sanford-Burnham Medical Research Institute reported having derived dermal papilla cells from human embryonic stem cells, transplanting them under the skin of immunodeficient hairless ("nude") mice, and having them turn into hair follicles and fur the critters up. In a press release, the principal investigator is quoted as having said “Our next step is to transplant human dermal papilla cells derived from human pluripotent stem cells back into human subjects. We are currently seeking partnerships to implement this final step.”

This is an area research that has a strong promise of being translated and available on the market in the very near future, in part because cell therapy is finally reaping the fruits of a long track record of prior research and are now being aggressive supported by biotech VC, Big Pharma, and national health research institutes like the NIH and the MRC: in that context, SENS Research Foundation's investment would do very little to advance the needle, and would run a high risk of being redundant to others' efforts. It's exactly in relatively neglected areas of rejuvenation research that we have leverage (in the proper, non-buzzword sense) to make a disproportionate dollar-for-dollar impact with our investments.

Also, while a cure for baldness would generate huge headlines and substantial kudos, it's already so generally accepted that alopecia is curable and that cell therapy will work for it that it won't constitute a particular coup for the "damage-repair" strategy. Cures, rock-solid preventive therapies, or truly breakthrough disease-modifying treatments for things that are currently being targeted by old-school, mess-with-metabolism approaches (diabetes, heart disease) and/or are regarded as essentially incurable (Alzheimer's, "aging") would be expected to have a much stronger impact in changing the research paradigm.

And, in general, I think that in a world of very limited funding availability and with 90,000 people literally dying every day of diseases brought on by degenerative aging processes (and many more being crippled, bereaved, or constrained), it behooves us to focus on things that actually cripple and kill people.

Posted by: Michael at June 18th, 2015 12:54 PM

If dermal papillae cells induce hair growth, then perhaps it is possible to just take their exosome secretion profile and use that as a drug instead of expensively deriving Dermal Papillae cells from induced pulripotent stem cells or embryonic stem cells.

Failing that, are there any miR-22 inhibitors out there?

Posted by: Jim at June 20th, 2015 10:38 PM

Jim, a cell performing its physiological function under a carefully-orchestrated, multi-component, regulated regime of feedback systems is likely to do a much better job of this than shoving one element of the regulatory system in to a target cell at some fixed dose that we happen to think works. Would you rather have functioning beta-cells, or insulin injections?

Posted by: Michael at June 23rd, 2015 11:07 AM

Here is another recent good research paper on microRNA and hair loss:
Hopefully big potential to help us in the future.

MicroRNA-214 controls skin and hair follicle development by modulating the activity of the Wnt pathway
J Cell Biology 2014 Nov 24; 207(4): 549–567.
Authors: Mohammed I. Ahmed,1,* Majid Alam,1,* Vladimir U. Emelianov,2 Krzysztof Poterlowicz,1 Ankit Patel,1 Andrey A. Sharov,2 Andrei N. Mardaryev,1 and Natalia V. Botchkareva 1
Abstract:
Skin development is governed by complex programs of gene activation and silencing, including microRNA-dependent modulation of gene expression. Here, we show that miR-214 regulates skin morphogenesis and hair follicle (HF) cycling by targeting β-catenin, a key component of the Wnt signaling pathway. miR-214 exhibits differential expression patterns in the skin epithelium, and its inducible overexpression in keratinocytes inhibited proliferation, which resulted in formation of fewer HFs with decreased hair bulb size and thinner hair production. The inhibitory effects of miR-214 on HF development and cycling were associated with altered activities of multiple signaling pathways, including decreased expression of key Wnt signaling mediators β-catenin and Lef-1, and were rescued by treatment with pharmacological Wnt activators. Finally, we identify β-catenin as one of the conserved miR-214 targets in keratinocytes. These data provide an important foundation for further analyses of miR-214 as a key regulator of Wnt pathway activity and stem cell functions during normal tissue homeostasis, regeneration, and aging.

Posted by: Bruck at March 4th, 2016 1:57 PM

as mentioned above once we can find a cure for aging we can cure all the things that will kill us so we need to focus on getting more money billions we all need to just look back at all our loved ones that are long past on and just maybe the whole world will come as a force to be delt with and then we will find a cure for death....while we are still alive....

Posted by: Hasan at November 25th, 2018 10:17 AM

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