Bernstein Medical Center for Hair Restoration

Study Confirms Importance of Dermal Sheath Stem Cells in Hair Growth Cycle

New research published in the journal Developmental Cell has confirmed the importance of dermal sheath stem cells in maintaining the hair growth cycle. ((Rahmani W, et al. Hair Follicle Dermal Stem Cells Regenerate the Dermal Sheath, Repopulate the Dermal Papilla, and Modulate Hair Type. Dev Cell. 2014 Dec 8;31(5):543-58.)) These cells, located around the lower portion of growing follicles, form the basis of an experimental treatment, being developed by Replicel Life Sciences, Inc., to regenerate hair-producing follicles. If successful, the treatment will be a game-changer for the hair restoration industry.

Colony of self-renewing dermal sheath cells

The study, published in December 2014, sought to confirm what had been indirect evidence of a type of stem cell residing in the dermal sheath (DS) that was said to replenish dermal papilla (DP) cells. The authors of the study suggest that they now have definitive evidence that new DP cells are derived from stem cells in the dermal sheath “cup” (DSC). This development clarifies the relationship between the DS and the DP and confirms that DSC cells play a critical role in hair follicle regeneration by repopulating the dermal papilla cells at the end of the telogen (resting) phase of the normal hair cycle.

Importance of the Dermal Sheath Cup Cells

The number of dermal papilla (DP) cells in a hair follicle has been found to be a determining factor as to when the anagen (growth) phase of the hair cycle is initiated. ((Chi W, Wu E, Morgan BA, et al. (2013). Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline. Development 140, 1676–1683.)) The gradual loss of DP cells over time results in a longer delay in the onset of the anagen phase; a longer telogen (resting) phase; and a hair follicle that shrivels and eventually disappears. This process, called miniaturization, plays out over multiple hair cycles and has been shown to be the primary contributor to androgenetic alopecia and eventual baldness. ((Randall VA. (2008). Androgens and hair growth. Dermatol. Ther. 21, 314–328.))

While dermal sheath cup (DSC) stem cells are known to be long-lived and self-renewing, it is not fully understood how they replicate or why the pool of DSC cells becomes depleted over time. We do know, however, that the gradual loss of DSC cells results in a failure to produce the necessary number of DP cells. And without enough DP cells to trigger the anagen phase, the follicle begins to miniaturize. It is clear that maintaining the population of DSC cells after each iteration of the hair cycle is very important in preserving and maintaining healthy and mature terminal hairs.

Replicel Reacts to the Study

The new data confirming the importance of the dermal sheath cup (DSC) cells was celebrated by researchers and executives at Replicel Life Sciences, Inc., who have been studying this issue for over a decade. Replicel is set to start phase II clinical trials of RCH-01, their proprietary treatment for androgenetic alopecia.

In the RCH-01 treatment, cloned DSC cells are injected into balding areas of the scalp where they are expected to reverse miniaturization and regenerate healthy, hair-producing follicles. Phase I trials of RCH-01, the results of which were published in 2012, showed that the treatment could produce promising results and that it was safe to administer. Six months after patients were treated with RCH-01, overall hair density increased by an average of 11.8% in ten patients out of 16. In two patients, overall hair density increased by more than 19%. There were no significant adverse safety events recorded. ((Lortkipanidze, N. Safety and Efficacy Study of Human Autologous Hair Follicle Cells to Treat Androgenetic Alopecia. In Clinicaltrials.gov. Retrieved July 26, 2012.)) Phase II clinical trials are set to begin in 2015, with data collection continuing for 39 months.

Through a 2013 agreement with Replicel, Japanese cosmetics giant Shiseido may introduce RCH-01 into the Asian market as early as 2018.

Image c/o Developmental Cell 31, 543–558, December 8, 2014 ª2014 Elsevier Inc.

Posted by Robert M. Bernstein M.D.

Laminin-511 Stimulates Dermal Papilla for New Hair Growth

Jing Gao, Mindy C. DeRouen, Chih-Hsin Chen, Michael Nguyen, et. al.
Genes & Development 22:2111-2124, 2008

The growth of a hair follicle from its developmental cell stage to a hair bearing follicle is through an interactive process between epidermal cells and those of the dermal papilla. It was found that Laminin-511 is instrumental in facilitating this process.

It has been felt that the extra-cellular protein Laminin is critical to both adhesion and the signaling process in hair development; however, the mechanism is not fully understood.

Through this study, it was shown that the signaling pathways introduced by the administration of noggin and sonic hedgehog alone were insufficient to develop a hair follicle. When Laminin-511 protein was introduced to the tissue culture, the dermal papilla developed. When the protein was inhibited, hair follicle growth again ceased. This information supports prior studies suggesting that Laminin is critical in the early stages of follicle cell development and is required for continued follicle development and growth.

This study reaffirms in vitro and in vivo studies in mice, the importance of Laminin-511 in the formation of dermal papilla to promote the development of more organized dermal papilla cells and the hair follicle development. It also suggests that there is a reciprocal mechanism between the signaling pathways of noggin and sonic hedgehog with Laminin-511.

Posted by Robert M. Bernstein M.D.

Strategies for Follicular Cell Implantation

by Jeff Teumer, PhD
Hair Transplant International Forum, Volume 18, Number 3, May/June 2008

Follicular cell implantation (FCI) is based on the ability of the dermal papilla (DP) cells, found at the bottom of hair follicles, to stimulate new hairs to form. DP cells can be grown and multiplied in a culture so that a very small number of cells can produce enough follicles to cover an entire bald scalp.

In order to produce new follicles, two types of cells must be present. The first is Keratinocytes, the major cell type in the hair follicle, and the second are dermal papillae cells (DP) which lie in the upper part of the dermis, just below the hair follicle. It appears that the DP cells can induce the overlying keratinocytes to form hair follicles. There are a number of proposed techniques for hair regeneration that use combinations of cells that are implanted in the skin. The two major techniques involve either transplanting dermal papillae cells by themselves into the skin or implanting them with keratinocytes. These techniques can be used with or without an associated matrix used to help orient the newly forming follicles.

Implanting Dermal Papillae Cells Alone

Implanting DP cells by themselves into the dermis, with the hope that they will cause the overlying skin cells (keratinocytes) to be transformed from normal skin cells into hair follicles. This method is called “follicular neo-genesis” since new hair is formed where none previously existed.
Cells of the dermal papillae are placed alongside miniaturized follicles. The transplanted cells would induce the keratinocytes of the miniaturized follicles to grow into a terminal hair. A potential advantage of this technique is that the existing miniaturized follicles already have the proper structure and orientation to produce a natural look growth.

Implanting Dermal Papillae with Keratinocytes

A mixed suspension of cultured keratinocytes and DP cells are implanted into the skin.
Keratinocytes and DP cells are cultured together such that full or partial hair formation takes place in a culture dish. These culture-grown hairs, or “proto-hairs,” are then implanted into the patient. The advantage of using a proto-hair is that there would be better control over the direction of hair growth because of the structural orientation of the proto-hair.

Cell Implantation using a Matrix

A variation of the above techniques is to use a matrix to help orient the implanted cells. This could be either an artificial matrix composed of materials such Dacron or it could be a biological matrix composed of collagen or other tissue components. The matrix would act like a scaffold to help cells organize to form a follicle. If the matrix were filamentous (like a hair) it could help direct the growth of the growing follicle. A matrix could be used with dermal papillae cells alone or in combination with cultured keratinocytes.

With all of the varied approaches for FCI, the aim is to combine keratinocytes and DP cells to efficiently and reproducibly generate thousands of follicles for hair restoration. In some cases, cells are combined in vivo and all of the hair formation must take place in the body after implantation, while in others, some hair formation takes place in culture before implantation.

Posted by Robert M. Bernstein M.D.