Telogen Phase of Hair Growth - Bernstein Medical - Center for Hair Restoration
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Two new studies researching a class of drugs called JAK inhibitors have shown that oral treatment results in significant hair regrowth in patients with alopecia areata, an autoimmune condition that causes non-scarring patches of localized hair loss. Currently there is no cure for alopecia areata, so the possibility of a safe, effective medication is welcome news for thousands of affected patients.

Background

Last year we wrote about how the two new FDA-approved drugs tofacitinib and ruxolitinib act as inhibitors of the family of enzymes called Janus kinase (JAK). ((Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, Clynes R, Christiano AM. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv. 2015 Oct; 1(9): e1500973.)) By inhibiting the JAK enzymes, the drugs disrupt intracellular communication to white blood cells, called “T lymphocytes,” and are thus useful in treating alopecia areata. The JAK inhibitors prevented the onset of the disease and reversed the condition, enabling hair to regrow in areas previously devoid of hair.

The 2015 study we referenced – led by renowned alopecia areata researcher Dr. Angela Christiano – showed that topical application of tofacitinib and ruxolitinib in mice resulted in the rapid transition of hair follicles from the telogen (resting) phase of the hair cycle to the anagen (growth) phase. The same study found that tofacitinib encouraged hair follicle development in clumped human dermal papilla (DP) cells, stem cells that are critical in the development of hair follicles. [1]

The Studies

The two new studies were published in September 2016 in the journal JCI Insight, a peer-reviewed journal dedicated to biomedical research.

Tofacitinib

The study of oral tofacitinib – by Crispin, Ko, et al – was a 2-center, open-label, single-arm trial; the first to systematically examine the efficacy of JAK inhibitors as a treatment for alopecia areata. ((Crispin MK, Ko J, Craiglow BG, Li S, Shankar G, Urban JR, Chen JC, Cerise JE, Jabbari A, Winge MG, Marinkovich MP, Christiano AM, Oro AE, King BA. Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata. JCI Insight. 2016;1(15):e89776. doi:10.1172/jci.insight.89776.)) In addition to studying alopecia areata (AA) patients with greater than 50% scalp hair loss, they tested the drug on patients with alopecia totalis (AT), which is the complete loss of scalp hair; alopecia universalis (AU), the loss of scalp and body hair; and ophiasis pattern alopecia areata, hair loss localized to the temporal and occipital scalp. After three months on 5mg tofacitinib citrate, 32% showed up to 50% improvement, and 32% showed greater than 50% improvement. When broken down by subtype of the condition, those with AA improved by 70% on average, those with ophiasis improved by 68%, AT by 11.8%, and AU by 10.5%. They found that following cessation of the treatment, all patients experienced a recurrence of hair loss after an average of 8.5 weeks. Additional trials are necessary to determine the optimal dosage regimen for providing the most long-lasting response.

Ruxolitinib

The study of ruxolitinib – by Mackay-Wiggan, Jabbari, et al – was an open-label clinical trial of 12 patients with moderate to severe alopecia areata. ((Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise J, Clark C, Ulerio G, Furniss M, Vaughan R, Christiano AM, Clynes R. Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata. JCI Insight. 2016;1(15):e89790. doi:10.1172/jci.insight.89790.)) The pilot study tested the use of 20mg oral ruxolitinib twice a day for three to six months; this was followed by three months of monitoring the patients without treatment. Despite the small sample size, the results were striking in that 75% of patients showed a strong response to the medication, with hair regrowth over 50%. After treatment, those who responded to the treatment exhibited a 92% reduction in hair loss. Seven of the nine responders achieved greater than 95% hair regrowth. After stopping treatment hair loss resumed; however, it did not reach the level of hair loss that was present before treatment. This proof-of-concept pilot study showed that ruxolitinib is a safe and effective in reversing the balding effects of alopecia areata.

Conclusion

After showing promise in previous research, scientists have now shown that JAK inhibitors have strong potential to cause substantial hair regrowth in people with alopecia areata; a condition that causes hair loss that can be socially awkward at best and cosmetically disfiguring in severe cases. More studies need to go forward in order to determine which of the two drugs – tofacitinib or ruxolitinib – will be the most effective treatment, and what the proper dosage is for long-term treatment. However, we are hopeful that a medication will be developed for broad use in treating alopecia areata patients.

The other major point of interest following the publication of the series of studies is the potential for JAK inhibitors to treat androgenetic alopecia, or common genetic hair loss. One area that is being discussed is the potential for JAK inhibitors, perhaps in the form of a topical treatment, to stimulate the transition of hair follicles from the resting phase to the growth phase of the hair cycle. Christiano’s research is examining the effects of JAK inhibitors on cultured dermal papilla (DP) spheres. If JAK inhibitors can be used to stimulate DP spheres to grow into mature hair follicles, it may enable hair multiplication techniques to become a viable treatment for common baldness.

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Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis
Researchers show how the normal hair cycle (left) is disrupted by DNA damage (center),
resulting in age-induced hair follicle miniaturization (right)

We have known for decades that the incidence of male pattern baldness increases with age. New research published in the February 2016 edition of the journal Science has shed light on why this is the case. Researchers examining the role of hair follicle stem cells (HFSC) in the hair growth cycle have found that accumulated DNA damage in these cells results in the depletion of a key signaling protein and the progressive miniaturization of the hair follicle (and eventual hair loss). ((Matsumura H, Mohri Y, Binh NT, et al. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science. 2016 Feb: Vol. 351, Issue 6273, p. 613.)) The study represents a breakthrough in our understanding of the cell aging process and could open new pathways for the treatment of not only hair loss but other age-related conditions as well.

Background: The Hair Growth Cycle

At any point in time, a hair follicle exists in one of three phases:

  • Anagen Phase – this is the “growth” phase in which the hair follicle is actively producing living hair. Anagen can last from two to seven years.
  • Catagen Phase – this is a short transitional phase in which hair growth stops, the middle of the follicle constricts, and the bottom of the follicle begins to form the “club.” The follicle also separates from the bloodstream. Catagen lasts two to three weeks.
  • Telogen Phase – this is the “resting” phase in which the clubbed hair detaches from the dermal papilla and is susceptible to falling out. Telogen lasts three to four months before hair follicle stem cells initiate a new anagen (growth) phase and the cycle repeats.

Stem Cells and the Hair Cycle

Normally, hair follicle stem cells (HFSC) perpetuate the hair cycle by initiating a new anagen (growth) phase after the telogen (resting) phase. But HFSC, like all cells, age over time. Included in this aging process is damage to DNA strands inside these cells due to spontaneous errors in DNA replication or those due to exposure to sunlight and other insults. While it has been well understood that hair follicle miniaturization occurs as a person ages and that damage to genetic material contributes to the process, the exact mechanism that ties cell aging to the disruption of the normal hair cycle was unknown. The recent study examines miniaturization from cell aging and distinguishes it from miniaturization caused by the effects of DHT.

Results of the Study

The key finding in this new research is that as hair follicle stem cells (HFSC) accumulate genetic damage over time, their store of a signaling protein called COL17A1 is depleted. The depletion of this key protein forces HFSC to differentiate into a common type of skin cell called a keratinocyte. By differentiating into keratinocytes, the population of HFSC gradually shrinks, there are fewer HFSC to initiate the anagen (growth) phase, and the telogen (resting) phase is extended. With a gradually longer telogen phase and shorter anagen phase, the follicle progressively miniaturizes. Eventually, the hair-producing follicle disappears leaving a bald scalp and the keratinocytes, which no longer serve a purpose in the hair growth cycle, are ejected from the skin.1 Click here to view the graphic that illustrates this process.

The authors of the study suggest that restoring COL17A1 levels, or halting their depletion, may prevent this aging-induced hair follicle miniaturization from occurring.1

With perhaps much broader significance, the study confirms the tight linkage between the instability of genetic material in stem cells (that can be due to environmental factors) and the shrinkage and functional decline seen in many organs as they age.

Conclusion

Progressive hair loss is a pervasive problem for males as they age. However, current treatments deal, exclusively, with hormone-induced miniaturization. The discovery of the mechanism behind age-induced miniaturization may result in a new avenue for the treatment of hair loss. More research into methods of boosting levels, or preventing the depletion, of COL17A1 may yield a hair loss therapy that targets this cause of hair loss.

Further, developing a better understanding of the cell aging process may open up new avenues of research into the causes of, and potential solutions to, the age-induced decline of major organs in the body.

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Image c/o Science

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Dr. Angela Christiano and her team of researchers at Columbia University studying the autoimmune disease alopecia areata, have shed new light on how to move hair follicles from their resting stage (telogen) into the growth stage (anagen) in which they can produce normal hairs. The study, published in the October issue of Science Advances, introduces the possibility of a new topical medication for hair growth stemming from a class of chemicals that block enzymes in the Janus kinase (JAK) family. ((Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, Clynes R, Christiano AM. Pharmacologic inhibition of JAK-STAT signaling promotes hair growth. Sci Adv. 2015 Oct; 1(9): e1500973.)) The findings on the topical application of JAK inhibitors have implications in the treatment of common hair loss as well as alopecia areata, which causes a non-scarring form of localized hair loss.

Scientists had, until now, tried unsuccessfully to use drugs to induce follicles en masse into the anagen phase. The two FDA-approved medications currently used to treat hair loss each use a different approach. Finasteride (Propecia) blocks the conversion of testosterone to dihydrotestosterone (DHT) – the hormone that causes genetically susceptible hair follicles to progressively shrink or miniaturize. Minoxidil (Rogaine) extends the anagen phase, thereby delaying the onset of hair follicle miniaturization. JAK inhibitors could develop into a third major medical option for the treatment of hair loss.

Background: Research Investigating Alopecia Areata

Dr. Christiano, herself diagnosed with alopecia areata, has made several significant breakthroughs involving hair loss and its treatment in the past. Bernstein Medical has written extensively about her study of alopecia areata, hair loss genetics, and hair cloning.

Building on initial research in 1998 implicating a type of white blood cell known as “T lymphocytes” in the development of alopecia areata, ((Gilhar A, Ullmann Y, Berkutzki T, Assy B, Kalish RS. Autoimmune hair loss (alopecia areata) transferred by T lymphocytes to human scalp explants on SCID mice. J Clin Invest. 1998 Jan 1; 101(1):62-7.)) Dr. Christiano and her team set out to find ways to modulate them. In research published in the September 2014 issue of Nature Medicine, they looked at two different FDA-approved chemicals, ruxolitinib and tofacitinib, and how they act as inhibitors of enzymes in the family Janus kinase (JAK). Inhibiting JAK cut off communication to the T cells. Without an accumulation of T cells, alopecia areata could not progress. ((Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, de Jong A, Harel S, DeStefano GM, Rothman L, Singh P, Petukhova L, Mackay-Wiggan J, Christiano AM, Clynes R. Alopecia areata is driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med. 2014 Sep; 20(9):1043-9.)) The JAK inhibitors both prevented the onset of the disease, and reversed the condition where it was already established.

The most surprising finding of this study concerned the effect of topically applying the inhibitors.

“We found that topical ruxolitinib and topical tofacitinib were both highly effective in reversing disease in treated lesions (applied to back skin). A full coat of hair emerged in the ruxolitinib- or tofacitinib-treated mice by 7 weeks of treatment, and we observed complete hair regrowth within 12 weeks following topical therapy.”2

Findings: JAK Inhibitors and Hair Growth in Normal Subjects

Having successfully tested JAK inhibitors against alopecia areata, Dr. Christiano and her team sought to investigate JAK inhibition on normal mice and humans.

The researchers applied solutions of tofacitinib and ruxolitinib to one side of the backs of mice with hair in the telogen phase, while the other side was treated with a control solution. Within seven days of treatment, each mouse saw robust hair growth on the treated side, while the control side did not. This indicates a rapid transition of the hair cycle from telogen (resting) to anagen (growth). Furthermore, they found that treatment with JAK inhibitors resulted in “significant proliferation” of hair follicle stem cells, indicating that the inhibitors activated progenitor stem cells within the follicles. The topical application of JAK inhibitors in mice unmistakably resulted in rapid onset of hair growth.

Next, the team looked at the effects of JAK inhibitors on cultured dermal papilla (DP) spheres. In 2013, Dr. Christiano achieved a breakthrough in using an ingenious technique, called a “hanging drop culture.” Using this process, her team caused dermal papilla cells to clump together in a spherical (tear drop) shaped configuration. They found that DP cells in this three-dimensional mass more easily communicate with one another and are then capable of forming new hair follicles. When cultured in a solution containing the JAK inhibitor, tofacitnib, the DP spheres showed an enhanced ability to induce hair follicle development in larger sizes and in significantly greater numbers.

Conclusion/Summary

Topical application of JAK inhibitors leads to the activation and proliferation of hair follicle stem cells and a rapid transition to the anagen phase of the hair growth cycle. This research could be the catalyst for the development of a new topical treatment for hair loss that could potentially benefit individuals who are not indicated for, or who have not seen a positive response from, traditional hair loss medications or are not candidates for hair transplantation. Additionally, JAK inhibitors may be developed into a topical treatment for alopecia areata and potentially other autoimmune conditions that cause localized hair loss or other skin problems. JAK inhibitors might even aid in the development of hair cloning techniques, which could effectively cure hair loss.

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Could a hormone that plays a critical role in red blood cell production also play a critical role in hair follicle production? According to a 2010 research report published in the Journal of Dermatological Science, this may be the case.

Erythropoietin Implicated In Hair Growth Regulation

The hormone in question is called Erythropoietin (EPO). It is produced in the kidneys in order to regulate red blood cell production. Recent studies have shown that EPO is also produced in a structure that surrounds and protects a hair follicle, the outer root sheath (ORS). Moreover, other studies have found that the EOP secreted by the ORS seems to target dermal papilla (DP) cells. DP cells play a critical role in regulating hair growth.

Because of these results, researchers have speculated that EPO may affect hair growth by acting on DP cells, but no direct evidence for this had ever been found – until now.

Evidence That EPO Affects Hair Growth in Vitro (Cell Cultures)

Strong evidence of EPO’s direct involvement in hair growth would be the discovery of EPO receptor sites (EPOR) on DP cells and a clear mechanism of how EPO affects changes in a DP cell (called cell signaling); this is exactly what researchers in the Republic of Korea ((Kang BM, Shin SH, Kwack MH, Shin H, Oh JW, Kim J, Moon C, Moon C, Kim JC, Kim MK, Sung YK. Erythropoietin promotes hair shaft growth in cultured human hair follicles and modulates hair growth in mice. J Dermatol Sci. 2010 Aug;59(2):86-90. doi: 10.1016/j.jdermsci.2010.04.015. Epub 2010 May 19.)) have found. Not only did they find direct evidence of EPO receptive sites but they also discovered the critical cell signaling mechanism: phosphorylated EPOR signaling pathway mediators.

In addition to discovering the signaling mechanism, they also showed using cell cultures that EPO causes both dermal papilla to proliferate and hair shafts of human hair follicles to elongate.

While the effects of EPO on DP and hair follicles were compelling, they only occurred in vitro (in cell cultures outside the body) and it is known that cells cultured on a flat surface behave significantly differently than cells that exist in situ, inside the organism (see Higgins and Christiano, Regenerative Medicine And Hair Loss: How Hair Follicle Culture Has Advanced Our Understanding Of Treatment Options For Androgenetic Alopecia).

Evidence That EPO Affects Hair Growth In Situ (In The Body)

In order to better answer the questions of whether and how EPO might directly affect hair growth in situ, the Korean researchers implanted EPO treated DP cells into mice and found that these treated cells not only moved hair follicles from their resting (telogen) phase into an active hair growth (anagen) phase but also prolonged a follicle’s active growth phase.

This is a significant finding since one of the mechanisms of male pattern baldness is DHT susceptible hair follicles entering into progressively longer periods of a telogen (resting) phase relative to an anagen (hair growth) phase. EPO, having the opposite effect on hair follicles, opens the door to treating this type of hair loss with existing EPO analogs and/or developing new erythropoietin biopharmaceuticals.

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