Hair Pigmentation Hair becomes pigmented as a result of a tighly coordinated program of melanin synthesisand transport from the hair bulb melanocytes to differentiating hair shaft keratinocytes. This process is strictly coupled to Ngen and ceases during catagen and telogen. Numerous signaling molecules, structural proteins, enzymes, co-factors, and transcriptional regulators control hair pigmentation.
Hair melanocyte Development Melanoblasts can be identified in the epidermis of human embryos at 50 days of estimated gesttional age before the onset of hair follicle morphogenesis. These Folliculare melanocytes originate in the neural crest and migrate first to the dermis and then epidermis. Commitment of neural crest cell to the melanocyte lineage is regulated by Pax3 and microphthalmia transcription factors (Mift), which stimulate the expression of dopachrome tautomerase [or tyrosinase-related potein 2 (Trp2)], an enzyme involved in melanin bio shynthesis that also functions as an early melanoblast development (migration into the dermis and epidermis) are controlled by signaling mechanisms actived through endothelin receptor type B and c-kit oncogene (c-kit) receptor, which are mutated in humans with Hirschprung disease and piebaldism, respectively, resulting information of unpigmented hairs. After entering the placode of the developing air follicle, melanoblasts proliferate and become melanogenically active synchronously with the onset of hair fiber formation. Experimental and genetic data suggest that migration of melanoblasts into the hair follicle and their development toward melanogenically active forms depend on stem cell factor(SCF)/c-kit signaling. SCF is ligand that binds to its receptor, c-kit. Pharmocologic blocade of c-kit during embryogenesis, as well as genetic ablation of SCF or c-kit in corresponding mouse mutants results in unpigmente hairs.
Hair Follicle Melanocyte Stem Cells and Pigment-Producing Melanocytes MSCs located in the hair follicle bulge generate progeny that repopulate the melanocytes in the new hair bulb formed at the onset of anagen. MSCs express Trp2, Bcl-2, PAx3, while other melagonic enzymes (tyrosinase, Trp1) and signaling molecules (c-kit, endothelin receptor type B, SOX 10, Mitf and Lef-1) are expressed at low levels. MSCs can be first detected in the bulge area during late stages of hair follicle morphogenesis and similarly to ephitelial stem cells they show bromodeoxyuridine-retainiing capacity. Bcl-2 deficiency may be compensated by overexpressions of SCF, which rescues loss of MSCs in the hair follicle bulge of Bcl-2 knockout mice. Melanogenically active melanocytes are located in the hair bulb
above the dermal papilla. These cells synthesize and transport melanin to hair shaft keratinocytes and express a full set of enzymes and other prooteins involved in melanin bioshyntesis including tyrisinase, Trp1, Trp2(in mice), and pMel17(in human).
Hair cycle-Dependent changes in Melanocytes Hair follicle melanocytes undergo substansial remodeling during hair follicle sycling. In telogen, hair follicle melanocytes are found in the bulge, secondary hair germ, and connective tissue. In humans, melanocytes in the telogen hair follicle do not express Trp1 or tyrosinase and do not proliferate. Melanocytes can be visualized by expression of pMel17. Some of these cells also express c-kit receptor, whereas others remain c-kit negative and represent MSCs. During early anagen, resting melanocytes proliferate, differentiate, and migrate within the hair follicle synchronously with regeneration of the hair follicle bulb. Hir follicle melanocytes are maximally proliferative during early and midanagen, and their transition to melanogenetic competence is accompanied by the appearance of Tr[ 1 and tyrosinase proteins. Similar to embryonic and early postnatal development, SFC/c-kit signaling plays a critical role in repopulation of the bulb with pigment-producing melanocytes. C-kit is expressed on proliferating, differentiating, and melanogenically active melanocytes, whereas overexpression of SCF in the epidermis of transgenic mice significantly increases the number of hair follicle melanocytes and their proliferative activity. Similarly, administration of the ACK45 antibody blocking c-kit signaling dramatically reduces melanocytes number and distribution of melanocytes, suggesting that MSCs are not dependent on SCF/c-kit. During catagen, melanogenic activity in the follicular melanocytes abruptly ceases. Immunohistocheical and electron microscopic data suggest that some pigment-producing melanocytes located above the follicular papilla undergo apoptosia, while others drop into the dermal papilla of the follicle. Molecular Control of Heir Color Follicular melanocytes synthesize pigment via a cascade of enzymatic conversions of phenylalanine or tyrosine into brown-black eumelanin or yellow pheomelanin that requires melanogenic enzymes (tyrosinase, Trp 1/2, y-glutamyl transpeptidase, peroxidase) and essential co-factors, such as 6-tetrahydrobiopterin. The balance between black and yellow pigment synthesis ( eumelanin and phomelanin, respectively) is regulated by signaling throught the melanocortin type 1 receptor (MC-1R) that has long been implicated in the control of hair color.
After binding to MC-1R,α melanocytes –stimulating hormone (α-MSH) stimulates adenylyl cyclase, resulting in elevation of intracellular cyclic adenosine monophosphate levels. This leads to increase of transcripsional activity of Mitf that stimulates synthesis of melanogenic enzymes (tyrosinase,Trp ½) involved in eumelanin formation. Pheomelanin synthesis In the hair follicle melanocytes of mice occurs when MC-R1 signaling is inhibited by Agouti signal protein (ASP) that competes with α-MSH in binding to MC-1R. In mice, ASP expression is positively regulated by BMP signaling, and transgenic mice overexpressing BMP antagonist Noggin show hair darkenring. Althought ASP is expressed in human skin, its role in human pigmentation remains unclear. Recent data also demonstrate exixtance of fully functional proopiomelanocortin/MC-1R system in human hair follicles: MC-1R is expressed by hair follicle melanocytes, whereas its ligands α-MSH and adrenocorticitropic hormone are able to promote proliferation, dentricity, and melanogenesis. Similar effects are seen with other proopimelanocortin-derived peptide, β-endorphin that interacts with µ-opiate receptor expressed by hair follicle melanocytes. However, signaling through the µ-opiate receptor may regulate haor pigmentation via modulating the activity of protein kinase C-β, a know positive regulator of melanogenesis.
Rambut Pigmentasi Rambut menjadi berpigmen sebagai hasil dari program terkoordinasi erat sintesis melanin dan transportasi dari melanosit bola rambut untuk membedakan keratinosit batang rambut. Proses ini secara ketat digabungkan ke Ngen dan berhenti selama catagen dan telogen. Banyak molekul sinyal, protein struktural, enzim, co-faktor, dan regulator transkripsi mengontrol pigmentasi rambut. Rambut Pengembangan melanosit Melanoblasts dapat diidentifikasi dalam epidermis embrio manusia pada 50 hari dari perkiraan usia gesttional sebelum timbulnya folikel rambut morfogenesis. Ini melanosit Folliculare berasal dari neural crest dan bermigrasi pertama yang dermis dan epidermis kemudian. Komitmen saraf sel puncak ke garis keturunan melanosit diatur oleh Pax3 dan faktor microphthalmia transkripsi (Mift), yang merangsang ekspresi dopachrome tautomerase [atau-tirosinase terkait potein 2 (Trp2)], enzim yang terlibat dalam melanin bio shynthesis yang juga berfungsi sebagai pengembangan melanoblast awal (migrasi ke dalam dermis dan epidermis) dikendalikan oleh sinyal mekanisme actived melalui reseptor endotelin tipe B dan ckit onkogen (c-kit) reseptor, yang bermutasi pada manusia dengan penyakit Hirschsprung dan piebaldism, masing-masing, sehingga informasi dari rambut tidak berpigmen. Setelah memasuki placode folikel udara berkembang, melanoblasts berkembang biak dan menjadi melanogenically aktif serentak dengan terjadinya pembentukan serat rambut. Eksperimental dan genetik data menunjukkan bahwa migrasi melanoblasts ke folikel rambut dan pengembangan mereka terhadap bentuk melanogenically aktif tergantung pada faktor sel induk (SCF) / c-kit signaling. SCF adalah ligan yang mengikat reseptor, c-kit. Blocade Pharmocologic dari c-kit selama embriogenesis, serta ablasi genetik dari SCF atau c-kit di sesuai hasil mutan tikus di rambut tidak berpigmen. Stem Sel rambut folikel melanosit dan Pigment-Memproduksi Melanosit
MSC terletak di tonjolan folikel rambut menghasilkan keturunan yang terisi kembali melanosit dalam bola rambut baru terbentuk pada awal anagen. MSC mengungkapkan Trp2, Bcl-2, Pax3, sementara enzim melagonic lainnya (tirosinase, Trp1) dan molekul sinyal (c-kit, endotelin jenis reseptor B, SOX 10, MITF dan Let-1) dinyatakan pada tingkat yang rendah. MSC dapat pertama kali terdeteksi di daerah tonjolan pada tahap akhir dari folikel rambut morfogenesis dan juga untuk ephitelial sel induk mereka menunjukkan kapasitas bromodeoxyuridine-retainiing. Bcl-2 defisiensi dapat dikompensasi oleh overexpressions dari SCF, yang menyelamatkan kehilangan MSC di tonjolan folikel rambut dari bcl-2 tikus knockout. Melanogenically melanosit aktif yang terletak di rambut bola di atas papilla dermal. Sel-sel ini mensintesis dan mengangkut melanin pada rambut poros keratinosit dan mengekspresikan set lengkap enzim dan prooteins lain yang terlibat dalam melanin bioshyntesis termasuk tyrisinase, Trp1, Trp2 (pada tikus), dan pMel17 (pada manusia).
Perubahan rambut siklus-Dependent di Melanosit Melanosit folikel rambut menjalani renovasi substansial selama folikel rambut sycling. Dalam telogen, melanosit folikel rambut yang ditemukan di tonjolan, kuman rambut sekunder, dan jaringan ikat. Pada manusia, melanosit di telogen folikel rambut tidak mengungkapkan Trp1 atau tirosinase dan tidak berkembang biak. Melanosit dapat divisualisasikan oleh ekspresi pMel17. Beberapa sel-sel ini juga mengekspresikan reseptor c-kit, sedangkan yang lain tetap c-kit negatif dan mewakili MSC. Selama anagen awal, melanosit istirahat berkembang biak, membedakan, dan bermigrasi dalam folikel rambut serentak dengan regenerasi bola folikel rambut. Hir folikel melanosit yang maksimal proliferatif selama awal dan pertengahan anagen, dan transisi mereka untuk melanogenetic kompetensi disertai dengan munculnya Tr [1 dan protein tirosinase. Mirip dengan pengembangan postnatal embrio dan awal, SFC / c-kit sinyal memainkan peran penting dalam repopulation dari bola dengan penghasil pigmen melanosit. C-kit diekspresikan pada berkembang biak, membedakan, dan melanosit melanogenically aktif, sedangkan berlebih dari SCF dalam epidermis tikus transgenik secara signifikan meningkatkan jumlah melanosit folikel rambut dan aktivitas proliferasi mereka. Demikian pula, administrasi antibodi ACK45 memblokir c-kit sinyal secara dramatis mengurangi jumlah dan distribusi melanosit melanosit, menunjukkan bahwa MSC tidak tergantung pada SCF / c-kit.
Selama catagen, aktivitas melanogenic di melanosit folikel tiba-tiba berhenti. Data mikroskopis Immunohistocheical dan elektron menunjukkan bahwa beberapa melanosit penghasil pigmen terletak di atas papilla folikel menjalani apoptosia, sementara yang lain jatuh ke papilla dermal folikel. Pengendalian molekul Pewaris Warna Melanosit folikel mensintesis pigmen melalui riam konversi enzimatik fenilalanin atau tirosin menjadi coklat-hitam eumelanin atau pheomelanin kuning yang membutuhkan enzim melanogenic (tirosinase, Trp 1/2, y-glutamil transpeptidase, peroksidase) dan penting co-faktor, seperti 6 -tetrahydrobiopterin. Keseimbangan antara hitam dan kuning sintesis pigmen (eumelanin dan phomelanin, masing-masing) diatur oleh sinyal pikir melanocortin tipe 1 reseptor (MC-1R) yang telah lama terlibat dalam kontrol warna rambut. Setelah mengikat MC-1R, melanosit α -stimulating hormon (α-MSH) merangsang adenilat siklase, yang mengakibatkan peningkatan tingkat adenosin monofosfat siklik intraseluler. Hal ini menyebabkan peningkatan aktivitas transcripsional dari MITF yang merangsang sintesis enzim melanogenic (tirosinase, Trp ½) terlibat dalam pembentukan eumelanin. Sintesis pheomelanin Dalam melanosit folikel rambut tikus terjadi ketika MC-R1 sinyal dihambat oleh protein sinyal Agouti (ASP) yang bersaing dengan α-MSH di mengikat MC-1R. Pada tikus, ekspresi ASP diatur secara positif oleh BMP signaling, dan tikus percobaan yang mengekspresikan BMP antagonis Noggin menunjukkan darkenring rambut. Walaupun ASP dinyatakan dalam kulit manusia, perannya dalam pigmentasi manusia masih belum jelas. Data terbaru juga menunjukkan exixtance dari proopiomelanocortin berfungsi penuh / sistem MC-1R di folikel rambut manusia: MC-1R diungkapkan oleh melanosit folikel rambut, sedangkan ligan yang α-MSH dan hormon adrenocorticitropic mampu mempromosikan proliferasi, dentricity, dan melanogenesis. Efek yang sama terlihat dengan proopimelanocortin diturunkan peptida, β-endorphin lainnya yang berinteraksi dengan reseptor μ-opiat diungkapkan oleh melanosit folikel rambut. Namun, sinyal melalui reseptor μ-opiat dapat mengatur Haor pigmentasi melalui modulasi aktivitas protein kinase C-β, yang tahu regulator positif melanogenesis.