Stem Cells that Control Skin and Hair Color


A research team at NYU Langone Medical Center has uncovered a pair of molecular signals that control the hair and skin color in mice and humans. Manipulation of these very signals may lead to therapies or even drugs to treat skin pigment disorders, such as vitiligo.

Vitiligo
Vitiligo

Vitiligo is somewhat disfiguring condition characterized by the loss of skin pigmentation, leaving a blotchy, white appearance. Finding ways to activate these two signaling pathways may provide clinicians with the means to mobilize the pigment-synthesizing stem cells that place pigment in skin structures and, potentially, repigment the pigment-bearing structures that were damaged in cases of vitiligo. Such treatment might also repigment grayed hair cells in older people, and even correct the discoloration that affects scars.

Workers in the laboratory of Mayumi Ito at the Ronald O. Perelman Department of Dermatology and the Department of Cell Biology showed that a skin-based stem cell population of pigment-producing cells, known as “melanocytes,” grow and regenerate in response to two molecular signals. The Endothelin receptor type B (EdnrB) protein is found on the surfaces of melanocytes. EdnrB signaling promotes the growth and differentiation of melanocyte stem cells (McSCs). Activation of EdnrB greatly enhances the regeneration of hair-based and epidermal-based melanocytes. However, EdnrB does act alone. Instead, the effect of EdnrB depends upon active Wnt signaling. This Wnt signal is initiated by the secretion of Wnt glycoproteins by the hair follicle cells.

This work was published in Cell Reports, April 2016 DOI: http://dx.doi.org/10.1016/j.celrep.2016.04.006.

Previous work on EdnrB has established that it plays a central role in blood vessel development. This work by Ito and his team is the first indication that pigment-producing melanocytes, which provide color to hair and skin, are controlled by this protein.

A lack of EdnrB signaling in mice caused premature graying of the hair. However, stimulating the EdnrB pathway resulted in a 15-fold increase in melanocyte stem cell pigment production, and by two months, the mice showed hyperpigmentation. In fact, wounded skin in these mice became pigmented upon healing.

Overexpression of Edn1 Promotes Upward Migration of McSCs and Generation of Epidermal Melanocytes following Wounding (A–D) Whole-mount image of X - gal - stained wound area of Dct-LacZ (control; A and B) and Tyr-CreER ; EdnrB fl/fl ; Dct-lacZ (C and D) at indicated days after re-epithelialization. (E–J) Double immunohistochemical staining of Dct and Ki67 in the bulge (E and H), upper hair follicle (F and I), and inter-follicular epidermis (G and J ) in control (E–G) and K14-rtTA ; TetO-Edn1-LacZ (Edn1; H–J) mice. (K–N) Whole - mount analyses of wound site (K and L) and de novo hair follicles (M and N) within wound site from control (K and M) and Edn1 mice (L and N) at 8 days after re-epithelialization. (O–R) Quantification of the number of Dct - LacZ+ cells in wound site (O), the percentage of Ki67+/Dct+ cells (P), the number of pigmented cells in wound site (Q), and the percentage of pigmented de novo hair (R), respectively. Dashed lines indicate periphery of wound site in (A) and (D) and boundary between epidermis and dermis in (E)–(J). Arrowheads show Dct - LacZ + cells in wound area in (A)–(D) and Ki67+/Dct+ cells (H)–(J). IFE, inter-follicular epidermis; UF, upper follicle. Data are presented as the mean ± SD. *p < 0.01; **p < 0.02; ***p < 0.05. The scale bar represents 1 mm in (A), 50 m m in (E), 200 m m in (K) and (L), and 100 m m in (M) and (N).
Overexpression of Edn1 Promotes Upward Migration of McSCs and Generation of Epidermal Melanocytes following Wounding (A–D) Whole-mount image of X-gal – stained wound area of
Dct-LacZ (control; A and B) and Tyr-CreER; EdnrB fl/fl; Dct-lacZ (C and D) at indicated days after
re-epithelialization. (E–J) Double immunohistochemical staining of Dct and Ki67 in the bulge (E and H), upper hair follicle (F and I), and inter-follicular epidermis (G and J) in control (E–G) and K14-rtTA;
TetO-Edn1-LacZ (Edn1; H–J) mice.  (K–N) Whole-mount analyses of wound site (K and L) and de novo hair follicles (M and N) within wound site from control (K and M) and Edn1 mice (L and N) at
8 days after re-epithelialization.  (O–R) Quantification of the number of Dct-LacZ+ cells in wound site (O), the percentage of Ki67+/Dct+ cells (P), the number of pigmented cells in wound site (Q),
and the percentage of pigmented de novo hair (R), respectively.  Dashed lines indicate periphery of wound site in (A) and (D) and boundary between epidermis and dermis in (E)–(J). Arrowheads show Dct-LacZ+ cells in wound area in (A)–(D) and Ki67+/Dct+ cells (H)–(J). IFE, inter-follicular epidermis; UF, upper follicle. Data are presented as the mean ± SD. *p < 0.01; **p < 0.02; ***p < 0.05.
The scale bar represents 1 mm in (A), 50 micrometer in (E), 200 micrometer in (K) and (L), and 100
micrometer in (M) and (N).

If the Wnt signaling pathway was blocked, stem cell growth and maturation sputtered and stalled and never got going, even when the EdnrB pathway was working properly. These mice had unpigmented fur (see E in figure below).

Loss of beta-catenin Function Suppresses Edn1-Mediated Effects on McSC Proliferation, Differentiation, and Upward Migration (A) Experimental scheme for treatment of Tyr-CreER ; b -catenin fl/fl ; K14-rtTA ; TetO-Edn1-LacZ ( b -cat cKO; Edn1 ) mice and control K14-rtTA ; TetO-Edn1- LacZ ( Edn1 ) mice. (B–E) Gross appearance of Edn1 (B and D) and b -cat cKO; Edn1 mice (C and E) at second (B and C) and third telogen (D and E). (F–K) Immunohistochemistry for indicated markers (F, G, I, and J) and bright- field image (H and K) of bulge/sHG region in skin sections from Edn1 mice (F–H) and b -cat cKO; Edn1 mice (I–K) at anagen II. (L–Q) Bright-field image (L–N) and Dct immunostaining of whole-mount wound site (O–Q) from Tyr-CreER ; b -catenin fl/fl ( b -cat cKO; L and O), Edn1 (M and P), and b -cat cKO; Edn1 mice (N and Q). (R and S) Quantification of the percentage of Dct+ cells positive for Ki67, Tyr, and pigmentation (R) and the number of Dct+ cells in wounded site (S). Dashed lines indicate border between hair follicle and dermis. Arrow- heads indicate double positive cells for indicated markers (F and G) and pigmented cells (H). Data are presented as the mean ± SD.*p<0.05;**p< 0.02; ***p < 0.001. The scale bar represents 1 cm in (B)–(E), 10 m min(F), and 200 m min(L). 1
Loss of beta-catenin Function Suppresses Edn1-Mediated Effects on McSC Proliferation, Differentiation, and Upward Migration
(A) Experimental scheme for treatment of
Tyr-CreER; beta-catenin fl/fl; K14-rtTA; TetO-Edn1-LacZ (beta-cat cKO; Edn1) mice and control K14-rtTA; TetO-Edn1-LacZ (Edn1) mice.
(B–E) Gross appearance of Edn1 (B and D) and
beta-cat cKO; Edn1 mice (C and E) at second (B and C) and third telogen (D and E). (F–K) Immunohistochemistry for indicated markers (F, G, I, and J) and bright-field image (H and K) of bulge/sHG region in skin sections from Edn1 mice (F–H) and beta-cat cKO; Edn1
mice (I–K) at anagen II. (L–Q) Bright-field image (L–N) and Dct immunostaining of whole-mount wound site (O–Q) from
Tyr-CreER; beta-catenin fl/fl (beta-cat cKO; L and O), Edn1 (M and P), and beta-cat cKO; Edn1 mice (N and Q). (R and S) Quantification of the percentage of Dct+ cells positive for Ki67, Tyr, and pigmentation (R) and the number of Dct+ cells in wounded site (S).
Dashed lines indicate border between hair follicle and dermis. Arrow-heads indicate double positive cells for indicated markers (F and G) and pigmented cells (H). Data are presented as the mean ± SD.*p<0.05;**p<
0.02; ***p < 0.001. The scale bar represents 1 cm in (B)–(E), 10 micrometers in (F), and 200 micrometer  in (L).

However, perhaps the most exciting finding for Ito and his colleagues was that Wnt-dependent, EdnrB signaling rescued the defects in melanocyte regeneration caused by loss of the Mc1R receptor. This is precisely the receptor that does not function properly in red-heads, which causes them to have red hair and very light skin that burns easily in the sun. These data suggest that Edn/EdnrB/Wnt signaling in McSCs can be used therapeutically to promote photoprotective-melanocyte regeneration in those patients with increased risk of skin cancers due to their very lightly colored skin.

Melanocyte Stem Cell Modeld

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Published by

mburatov

Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).