Bernstein Medical - Center for Hair Restoration - Dermal Papilla
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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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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.

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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

  1. 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.
  2. 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

  1. A mixed suspension of cultured keratinocytes and DP cells are implanted into the skin.
  2. 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

  1. 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.

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