The Yin Yang of human hair follicle, A question of balance

Transcription

1 The Yin Yang of human hair follicle, A question of balance Bruno A.Bernard, Dr.es Sci., L Oréal Fellow, Scientific Directorate L Oréal R & I, Asnières, France Yang and light Yin and shade

2 The hair follicle has a unique behavior, under opposite influences throughout its entire life cycle. The hair follicle is a true paradigm of tissue homeostasis

3 Anatomy and properties of human hair follicle A few key numbers à follicles / scalp Hair fiber production rate: 0.3 mm/day, 1 cm/month Dimensions: Length: 4 mm Diameter: mm pilosebaceous unit: 1 hair follicle 2-3 sebaceous glands 1 apocrine gland(sweat) anagen /telogen Ratio : 85/15

4 The hair follicle morphogenesis is the result of ectodermal / mesenchymal cross-talk, starting at the 3 rd month of pregnancy +: Wnt, -cat, LEF1 FGF, TGF 2, Noggin MSX1/2, EDA/EDAR Delta1/Notch1 ---: BMP2/4, Delta1/Notch1 Wnt PDGF-A, Shh +: Shh, Wnt TGF /EGFR ETS2 -: Klotho, APCDD1 Notch1, BMP2/4 Wnt3, LEF1, WHN MOVO1, HOXC13 MSX1/2

5 Where does hair follicle pattern come from?

6 Where does hair follicle pattern come from? Reaction-Diffusion: Local activation (Wnt) and long range inhibition (DKK1) Wnt DKK1 H.Meinhardt & A.Gierer, Bioessays 2000, 22: T.Schlake & S.Sick, Cell Adhesion & Migration 2007, 1: J.B.A.Green & J.Sharpe, Development 2015, 142:

7 The hair cycle: a unique feature of hair follicle TNF, ER, Dsg3 3 weeks 3 months STAT3 Shh, Wnt, LEF-1, Noggin, BMP2/4 FGF18 Catagen Telogen Hairless, VDR RXR, hairless FGF5, TGF 1 3 years Anagen Neogen Wnt, Notch, LEF-1, FoxN1, HOXC13 GATA3 HGF IGF-1, FGF7, TGFb2

8 FGFs control hair cycle Imamura T. Biol Pharm Bull. 2014,37:1081-9

9 A study was carried out over a period of 14 years in a group of 10 normal and alopecic male volunteers By using the phototrichogram technique, 9000 hair cycles were recorded 930 hair follicles were followed monthly J.Halloy, B.A. Bernard, G. Loussouarn & A. Goldbeter, Proc. Natl. Acad. Sci. U.S.A. 2000, 97 : J.Halloy, B.A. Bernard, G. Loussouarn & A. Goldbeter, J. Theor.Biol. 2000, 214 :

10 Activity level A new concept: the hair follicle, a bistable organ n - 1 n n + 1 ASS Anagen Neogen Catagen DSS Telogen + Kenogen i i + 1 Time Bernard B.A., the human hair follicle, a bistable organ. 2012, 21:401-3

11 The dermal papilla, a key controller n-1 n Telogen + Kenogen (n 1) DP Neogen induction by secretion of morphogens Neogen Anagen Buffering of morphogenetic signals by expending ECM Catagen Telogen + Kenogen Bernard B.A., the human hair follicle, a bistable organ. Exp.Dermatol.2012, 21:401-3

12 New activators and inhibitors in the hair follicle dynamics: targeting stem cells state of competence BMP FGF18 WNT FGF7 TGFb2 Plikus MV, J.Invest.Dermatol May;132(5): Oshimori N, Fuchs E., Cell Stem Cell 2012, 10 :63-75 Greco V, Chen T, Rendl M et al., Cell Stem Cell 2009, 4 : Kimura-Ueki M, Oda Y, Olk J et al., J.Invest.Dermatol.2012, 132: Botchkarev W, Botchkareva NV, Nakamura M et al., FASEB J 2001, 15:

13 hair growth is controlled by a number of pathways i.e. Prostaglandin metabolism

14 PGE 2 and PGF 2a are endogenously synthesized by human hair follicle and mainly oriented to local production of PGF 2a AA COX-1 PGH 2 mpges-2 AKR1C3 (PGFS) PGD 2 PGE 2 CBR1 PGF 2 a AKR1C3 (PGFS) L.Colombe, A.Vindrios, J.F.Michelet & B.A.Bernard. Exp.Dermatol. 2007, 16: 762-9

15 The whole spectrum of Prostaglandins can be synthesized in human hair follicle PGDS cpges mpges-1 mpges-2 AA COX-1 PGI 2 PGIS TXAS PGH 2 TXA 2 PGD 2 PGE 2 CBR1 AKR1C3 (PGFS) PGF 2 a 15-PGDH (NAD+) 15 keto-pgi 2 15-PGDH (NAD+) 15-PGDH (NAD+) AKR1C3 (PGFS) 15-PGDH (NAD+) 15 keto-pgd 15 keto-pgf 2 a 2 15 keto-pge 2 15-PGDH (NAD+) 15 keto-txa 2 DEACTIVATED PRODUCTS

16 All PGs receptors are expressed in human hair follicle L.Colombe, J.F.Michelet & B.A.Bernard. Exp.Dermatol. 2008, 17:63-72

17 Human hair follicle is endowed with a full prostaglandin network FP-R EP1-R EP2-R EP4-R EP3-R Gq Free Arachidonic acid cphospholipase A 2 PGF 2 PGFS PGESs PGE 2 Gq PGIS Gs Gi Gs PGI 2 Gq Gs IP-R COX-1 PGH 2 PGDS DP1-R TXA 2 S TP-R Gq PGD 2 DP2-R Gs TXA 2 Gi

18 Bimatoprost stimulates in vitro growth of human hair follicle K.G.Khidhir, D.F.Woodward, N.P.Fario et al., FASEB J. 2013, 27:557-67

19 PGD2 inhibits hair growth and is increased in balding scalp AA COX-1 PGD 2 PGH 2 mpges-2 PGE 2 AKR1C3 (PGFS) CBR1 PGF 2 a AKR1C3 (PGFS) PGF 2 a PGD 2 Garza LA et al., Sci Transl Med Mar 21;4(126):126ra34

20 Hair pigmentation is controlled by the pigmentation unit Hair greying is due to a decline of melanocyte progenitor reservoir

21 The pigmentation unit is responsible for hair pigmentation

22 The hair follicle contains 2 types of melanocytes Reservoir (dormant state) pmel-17 Tyrosinase (-) TRP1(-) Pigmentation unit (active state) pmel-17 Tyrosinase TRP1

23 Melanocyte activity is controlled by its microenvironment 2 niches? NR Repressive Niche Permissive Niche (1) (5) NP

24 The pigmentation unit degenerates during catagen phase and regenerates from the reservoir in early neogen 3 weeks 3 months Catagen Telogen Anagen VI Neogen 3 years

25 The pigmentation unit degenerates during catagen phase and regenerates from the reservoir in early neogen a b c A Ki-67 (green) pmel-17 (red) Keratin pan (blue) S.Commo & B.A.Bernard, Pigment Cell Res. 2000, 13 :253-9

26 A transitory Niche allows for melanocyte migration and proliferation in early neogen Repressive Niche (NR) Transitory Niche (NT) Permissive Niche (NP)

27 The hair follicle melanocyte cycle? Telogen NR Catagen NT Anagen III/IV NR Anagen VI NP Pigmented hair Commo S, Bernard BA, Pigment Cell Res. 2000, 13 :253-9

28 In grey hair, melanocytes are still active pmel-17 + Tyrosinase + Melanin transfer TRP1 +

29 Hair graying is due to a progressive decline in progenitor reservoir A B C D E a a a a a b b b b b c c c c c S.Commo S, O.Gaillard &.Bernard BA, Br.J.Dermatol. 2004,150,435-43

30 Melanocyte progressive decline coincides with the absence of TRP-2 expression - Maintenance - Disappearance -Mélanocytes TRP2 (+) -Mélanocytes TRP2 (-) S.Commo, O.Gaillard, S.Thibaut & B.A.Bernard, Pigment Cell Res. 2004, 17:488-97

31 TRP-2 expression protects melanocytes from oxidative stress (H 2 O 2 ) viability wt clone 1 clone 2 wt [H2O2] 0 µm 50 µm 75 µm 100 µm TRP2 wt Vimentine cl.2 Q.Michard, S.Commo, J.P.Belaidi et al., Free Rad Biol Med 2008, 44:

32 A number of actors promote hair growth while others promote catagen

33 Androgen receptors are expressed in human hair follicle, 5a reductase is active FIGURE 2 C.Gerst et al., Exp.Dermatol. 2002, 11:52-58

34 Testosterone (5µg/ml) inhibits hair growth Caffeine restores hair growth Fischer TW, Hipler UC, Elsner P Int J Dermatol 2007, 46:27-35

35 IL-1 inhibits hair growth in vitro IL-1 induces the pro-inflammatory cascade Y.Mahé et al., Skin Pharmacol. 1996, 9:

36 New inhibitors of hair growth, Involved in androgenic alopecia IL-6 Kwack MH, Ahn JS, Kim MK et al., J.Invest.Dermatol 2012, 132 :43-9

37 TGFb1 inhibits hair growth and promotes catagen TGF- 1 Inui S, Itami S. J Dermatol Sci. 2011, 61:1-6 Collin C., et al. Int.J.Cosm.Sci. 2006, 28:

38 New inhibitors of hair growth, Involved in androgenic alopecia DKK1 l-ascorbic acid 2-phosphate represses the dihydrotestosterone induced DKK1 expression in human balding dermal papilla Cells Kwack MH, Kim MK, Kim JC, Sung YK, Exp Dermatol 2010, 19: Inui S, Itami S, J.Dermatol.Sci 2011, 61:1-6

39 H4 and H2A Histones inhibit hair growth Shib sh, Joo HW, Kim MK et al., Exp.Dermatol 2012, 21: 956-8

40 Interferon-g inhibits hair growth, And induces catagen transition Ito T, Ito N, Saathoff M, Bettermann A et al. Br J Dermatol. 2005, 152:623-31

41 Brain-derived neurotrophic factor inhibits hair growth, And induces catagen transition Peters EM, Hansen MG, Overall RW, et al.j Invest Dermatol. 2005, 124:675-85

42 Transient Receptor Potential Vanilloid TRPV-3 activation inhibits hair growth, and induces catagen transition Borbíró I, Lisztes E, Tóth BI et al., J Invest Dermatol. 2011, 131:

43 CGRP induces catagen transition Samuelov L, Kinori M, Bertolini M, Paus R. J Dermatol Sci. 2012, 67:153-5

44 Endo- and exocannabinoids inhibit hair growth Telek A, Bíró T, Bodó E etal. FASEB J Nov;21(13):

45 size increase (mm) 6-O-glucose linoleate (4.91 g/l) and glucose (2 g/l) both support in vitro hair growth and survival GROWTH SURVIVAL 1,4 1,2 1, ,8 0,6 0,4 w illiam's w /o SP94 4,91 g/l Vit.F 3,11 g/l D-Glucose 2 g/l 0,8 0,6 0,4 w illiam's w /o SP94 4,91 g/l Vit.F 3,11 g/l D-Glucose 2 gl 0,2 0, days days Vingler P, Gautier B, Dalko M et al.. Int.J.Cosm.Sci. 2007, 29 :85-95

46 Arginine, a semi-essential amino acid, supports hair growth Michelet JF, Bernard BA, Juchaux F et al. 28 th IFSCC Meeting Proceedings 2014, pp1123-8

47 Arginine is involved in 2 pathways L-ARGININE NO

48 Spermidine promotes hair growth Ramot Y, Tiede S, Bíró T et al. PLoS One. 2011;6(7):e22564.

49 1,25OH 2 D 3 stimulates hair growth, and prevents catagen transition Billoni N, Gautier B, Mahé Y, Bernard BA. Arch Dermatol Venereol 1997, 77:350-5

50 T3 stimulates hair growth, and prevents catagen transition Billoni N, Buan B, Gautier B et al. Br J Dermatol. 2000, 142:645-52

51 Carnitine tartrate and IGF-1 promote hair growth, And prevents catagen transition Ahn SY, Pi LQ, Hwang ST, Lee WS, Ann Dermatol. 2012, 24: Foitzik K, Hoting E, Förster T et al., Exp Dermatol. 2007, 16:936-45

52 IGF1 stimulates hair growth, and prevents catagen transition Ahn SY, Pi LQ, Hwang ST, Lee WS. Ann Dermatol. 2012, 24:26-31

53 Cyclosporin A stimulates hair growth, And prevents catagen transition Hawkshaw NJ, Haslam IS, Ansell DM et al., J.Invest.Dermatol 2015, 135:

54 The Yin Yang of human hair follicle, A question of balance T3 Vit D3 FGF7 IGF1 TGF 2 Follistatin /noggin Wnt Arginine Glucose Glutamine Spermidine Carnitine tartrate Cyclosporine A Androgens Estrogens FGF5 FGF18 TGF 1 BMP2/4 DKK1 BNDF IL1a IL6 Interferon g SP, CGRP Exo-/endocannabinoids Histones H2a / H4

55 Thank you for your Attention