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Biology of melanocyte   Torello Lotti Department of Dermatologic Science University of Florence, Italy The International S...
<ul><li>A typical melanocyte is 7 μm in lenght . </li></ul>From : http://www.beautymagonline.com/pages/epidermal_turnover....
Melanocyte cytology <ul><li>After delivery, dendrites  </li></ul><ul><li>are maintained by the mitosis of the existing one...
Melanocyte cytology <ul><li>Abundant rough endoplasmic reticulum (RER). </li></ul><ul><li>Well-developed Golgi  apparatus....
Melanocyte cytology <ul><li>Early stage melanosomes are characterized morphologically by intralumenal fibrils upon which m...
Confocal photograph  showing melanosome (yellow), actin (red) and microtubules (violet)
Melanosome  in motion: filamentous actin (red), microtubules (blue) and melansomes (green)
Melanocytes  distribution <ul><li>Melanocytes of the epidermis </li></ul><ul><li>Melanocytes migration from the neural cre...
Melanocytes precursors, knew as melanoblasts,  are formed in the  the neural crest:  in the 11th week of fetal life, they ...
-  Melanocytes   migration  - <ul><li>Section of a mouse embryo at 11.5 days of gestation: melanoblasts and melanocytes (i...
In human epidermic, melanocyte rside on the basement membrane, at the epidermal–dermal junction, and  they form a close as...
Each melanocyte  makes contact  with  around 30-40  keratinocytes. This constitutes the  epidermal-melanin  unit. Epiderma...
-  Melanocyte of the epidermis  - Immunohistochemical analysis  :  melanocytes are identified by using the marker D5, whic...
 
Longevity and resistance to apoptosis make melanocytes vulnerable to  mutations that arise over the years, particularly du...
Multipotent epidermal stem cells exist in the bulge region, at the bottom of the permanent portion of the follicle -  Mela...
- Melanocyte of the eye - <ul><li>Uveal melanocytes (UM) are differentiated melanocytes that originate from the neural cre...
- Melanocyte of the eye - <ul><li>Melanin has the ability to bind organic  </li></ul><ul><li>amines and metal ions: this r...
- Melanocyte of the ear - <ul><li>COCHLEA </li></ul><ul><li>Melanocytes are present as intermediate cells in the stria vas...
<ul><li>Melanocytes have been identified in the brain and leptomeninges, and may have  </li></ul><ul><li>many neuroendocri...
- Melanocyte of the heart - <ul><li>Melanocytes have been identified in the  valves  and  septa  of the heart and their  <...
<ul><li>It has been recently demonstrated that melanin biosynthesis takes place in the  </li></ul><ul><li>visceral adipose...
Summing up….  Locations and functions of melanocytes  HAIR FOLLICLE Melanocyte stem cell reservoir for skin. Hair pigmenta...
And also….
<ul><li>In lymphangioleiomyomatosis (LAM), muscle cells  </li></ul><ul><li>revert towards their developmental origins and ...
Melanocyte  functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Reserve stem cell </li></ul><ul><li>...
<ul><li>Melanocytes are cells specialized in the synthesis of the pigment  melanin   </li></ul>Melanogenesis <ul><li>The n...
<ul><li>Eumelanin, the best-know form of melanin, exists in two forms:  </li></ul><ul><li>Black melanin :  produces black ...
<ul><li>Pheomelanin produces reddish colours of hair, eye and skin.  </li></ul>PHEOMELANIN   <ul><li>Pheomelanin is more a...
Eumelanin is a nitrogenous and  insoluble pigment.  Pheomelanin is a sulfur-containing  and alkali-soluble pigment. EUMELA...
<ul><li>Individual melanocyte can synthesize  </li></ul><ul><li>both eu- and pheomelanin. </li></ul><ul><li>The synthesis ...
Both melanins derive from a common tyrosinase-dependent pathway with the same precursor, tyrosine. The obligatory step is ...
NEUROMELANIN   <ul><li>Neuromelanin is the dark pigment that produces a black colour in certain parts of  </li></ul><ul><l...
Melanocyte  functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Tanning </li></ul>
<ul><li>Tanning  results from a complex signalling pathway involving  </li></ul><ul><li>keratinocytes  and  melanocytes . ...
Miller AJ, Tsao H.   New Insights into Pigmentary Pathways and Skin Cancer.   The British Journal of Dermatology 2010;162(...
<ul><li>Ultraviolet (UV) radiation reaching keratinocytes  </li></ul><ul><li>leads to the production of a large number of ...
2. GENE TRANSCRIPTION <ul><li>MSH secreted from keratinocytes  binds to  melanocortin-1 receptor (MC1R)  on nearby melanoc...
3. PIGMENT SYNTHESIS <ul><li>Melanin production occurs predominantly in a  </li></ul><ul><li>lysosome-like structure  know...
Sinthesis passages of eu- and pheomelanin from tyrosine
Melanosomes are formed from two sources: - In the Smooth Endoplasmic Reticulum (SER), pre-melanosomes are produced by coal...
Localization of melanogenesis phases within the melanocyte <ul><li>Stage I to IV melanosomes are formed in cytosol and dis...
Post-Golgi transport of melanosomes in melanocyte citosol
<ul><li>On the keratinocyte side, the protease- activated receptor-2 (PAR2), a seven-transmembrane receptor  on keratinocy...
Once in keratinocytes, melanosomes are distributed and  -in response to UVR- positioned strategically over the ‘sun-expose...
Melanocyte  functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Autocrine/paracrine function </li></...
Summary of the major participants in the paracrine/autocrine network  that regulates melanocyte functions and survival.
Factors of the paracrine/autocrine network that regulates melanocyte functions, proliferation and survival, with their cel...
Key molecules and signaling pathways implicated  in melanocyte-keratinocyte interactions
Role of ET-1 and melanocortins in the DNA Damage Response Abdel-Malek ZA, Swope VB. Epidermal melanocytes: regulation of t...
Tsatmali M, Ancas J, Thody JA. Melanocyte functions and its control by melanocortin peptides. J Histoc & Cytochemistry 200...
Corticotropin Releasing Hormon central role in the skin response to stress Slominski A, Wortsman J, Pisarchik A, et al. Cu...
<ul><li>Human melanocytes express FP receptor (the receptor for PGF2 α ) in vitro and in vivo, and expression of this rece...
Melanocyte  functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Tanning </li></ul><ul><li>Autocrine/...
Melanocyte of the hair follicle <ul><li>Melanocyte Stem Cell  ( MSCs ) and hair follicle stem cells (SCs) reside in a comm...
<ul><li>In   catagen ,  all cells of the lower HF, including the mature melanocytes and rapidly cycling transit-amplifying...
Melanocyte  functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Reserve stem cells </li></ul><ul><li...
<ul><li>Melanocytes and melanin play critical roles during embryonic development. </li></ul><ul><li>This can be seen in in...
<ul><li>Melanocytes are not simply melanin-producing cells, but have several  </li></ul><ul><li>functions </li></ul><ul><l...
Co-culture of human epidermal keratinocytes (red) and melanocytes (green), showing melanosome transfer into keratinocytes ...
… for your attention.  yo for your for attention…. Thank you… www.torellolotti.it professor @ torellolotti.it
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Biology of melanocyte - Professor Torello Lotti, MD - University G.Marconi, Rome, Italy - and Linda Tognetti, MD - Department of Dermatologic Sciences University of Florence, Italy

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Although almost everyone has the same amount of melanocytes, the amount and size of the melanosomes and melanin particles produced can differ immensely in humans, resulting in the different races of the world. Dendritic prolongations take contact with nearby keratinocytes, and serve as melanosomes carriers.

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Biology of melanocyte - Professor Torello Lotti, MD - University G.Marconi, Rome, Italy - and Linda Tognetti, MD - Department of Dermatologic Sciences University of Florence, Italy

  1. 1. Biology of melanocyte Torello Lotti Department of Dermatologic Science University of Florence, Italy The International School of Vitiligo & Pigmentary Disorders Barcelona, 2-5 November 2011
  2. 2. <ul><li>A typical melanocyte is 7 μm in lenght . </li></ul>From : http://www.beautymagonline.com/pages/epidermal_turnover.htm Melanocyte cytology DIMENSION AND NUMBER <ul><li>Melanocytes comprise from 5% to 10% of the cells in the basal layer of epidermis. </li></ul><ul><li>There are typically between 1000 and 2000 melanocytes per mm2 of skin. </li></ul><ul><li>Although almost everyone has the same amount of melanocytes, the amount and size of the melanosomes and melanin particles produced can differ immensely in humans, resulting in the different races of the world. </li></ul>From: http://news.softpedia.com/news/12-of-the-DNA-Differs-Amongst-Human-Races-and-Populations-40872.shtml
  3. 3. Melanocyte cytology <ul><li>After delivery, dendrites </li></ul><ul><li>are maintained by the mitosis of the existing ones. . </li></ul><ul><li>Dendritic prolongations take contact with nearby keratinocytes, and serve as melanosomes carriers. </li></ul><ul><li>Melanocytes have a round, slightly pigmented cell body with numerous dendrites stemming from it. </li></ul>From: http://www.chups.jussieu.fr/polys/histo/TPhis/imagespoly2&Melanocyte.jpg.11.html DENDRITES
  4. 4. Melanocyte cytology <ul><li>Abundant rough endoplasmic reticulum (RER). </li></ul><ul><li>Well-developed Golgi apparatus. </li></ul><ul><li>Melanocytes are not attached to neighboring cells by desmosomes. </li></ul><ul><li>The lack mechanisms of cell union, typical of pavement epithelial cells, gives them the characteristic disaggregation appearance. </li></ul>Melanocyte from black human skin . From: http://bioeducate.ascb.org/images/FawcettTheCellPDFs/FawcettTheCellChapter11.pdf . ORGANELLES
  5. 5. Melanocyte cytology <ul><li>Early stage melanosomes are characterized morphologically by intralumenal fibrils upon which melanins are deposited in later stages. </li></ul><ul><li>The integral membrane protein Pmel17 is a component of the fibrils, can nucleate fibril formation in the absence of other pigment cell-specific proteins, and forms amyloid-like fibrils in vitro. </li></ul><ul><li>MELANOSOMES </li></ul><ul><li>Melanosomes are ellipsoid lysosome-related organelles (LROs), around 0,2-0,7 μ m long and limited by a membrane, filled with melanin and proteins. </li></ul><ul><li>Giant melanosomes have been in found in nevi: they can reach 5 μ m dimension. </li></ul><ul><li>Melanosome transport requires the microtubule and actin cytoskeleton. </li></ul>Melanosomes (green) marked with TRP-1.
  6. 6. Confocal photograph showing melanosome (yellow), actin (red) and microtubules (violet)
  7. 7. Melanosome in motion: filamentous actin (red), microtubules (blue) and melansomes (green)
  8. 8. Melanocytes distribution <ul><li>Melanocytes of the epidermis </li></ul><ul><li>Melanocytes migration from the neural crest </li></ul><ul><li>Melanocytes of the hair follicle </li></ul><ul><li>Melanocytes of the ear </li></ul><ul><li>Melanocytes of the brain </li></ul><ul><li>Melanocytes of the eye </li></ul><ul><li>Melanocytes of the heart </li></ul><ul><li>Melanocytes of the adipose tissue </li></ul>
  9. 9. Melanocytes precursors, knew as melanoblasts, are formed in the the neural crest: in the 11th week of fetal life, they migrate to various sites, where they proliferate and then differentiate into mature melanocyte. - Melanocytes migration - <ul><li>Melanocytes reside in: </li></ul><ul><li>skin </li></ul><ul><li>(epidermis and hair follicle) </li></ul><ul><li>inner ear </li></ul><ul><li>eye (choroid and retina) </li></ul><ul><li>brain and leptomeninges </li></ul>
  10. 10. - Melanocytes migration - <ul><li>Section of a mouse embryo at 11.5 days of gestation: melanoblasts and melanocytes (in blue) are migrating down from the neural crest derived cells along the spinal column and brain. </li></ul><ul><li>Melanocytes are usually identified by their expression of specific proteins (e.g.,tyrosinase (TYR), TYRP1, DCT, Pmel17/gp100, MART-1 and/or MITF). </li></ul><ul><li>Melanoblasts are more difficult to identify since they don’t produce melanin, therefore don’t usually express those markers; only occasionally DCT and/or KIT are detectable. </li></ul>
  11. 11. In human epidermic, melanocyte rside on the basement membrane, at the epidermal–dermal junction, and they form a close association with keratinocytes via their dendrites - Melanocyte of the epidermis -
  12. 12. Each melanocyte makes contact with around 30-40 keratinocytes. This constitutes the epidermal-melanin unit. Epidermal Melanin Unit 36 K KLM Unit 53 K - Melanocyte of the epidermis -
  13. 13. - Melanocyte of the epidermis - Immunohistochemical analysis : melanocytes are identified by using the marker D5, which stains the nuclear transcription factor. Haematoxylin and eosin stain of human skin: normal melanocytes have smaller nuclei and inconspicuous cytoplasm compared with the surrounding keratinocytes.
  14. 15. Longevity and resistance to apoptosis make melanocytes vulnerable to mutations that arise over the years, particularly due to sun exposure, and might culminate in melanoma formation in high-risk individuals. . Immune suppression INITIATION PROMOTION Eicosanoid production DNA DAMAGE PRE CANCER Displastic nevi Reactive O2 species CANCER Gene mutation Common nevi MELANOMA - Melanocyte of the epidermis -
  15. 16. Multipotent epidermal stem cells exist in the bulge region, at the bottom of the permanent portion of the follicle - Melanocytes in the hair follicle - Differentiated melanocyte reside in the hair bulb
  16. 17. - Melanocyte of the eye - <ul><li>Uveal melanocytes (UM) are differentiated melanocytes that originate from the neural crest. </li></ul><ul><li>Retinal pigment epithelium (RPE) is a distinct type of melanocyte-like, that develop in situ from the optic cup of the brain, and is specifically present only as a single layer of cells lying behind the retina </li></ul><ul><li>UM and RPE are located in the middle (choroid) and inner (retinal) eye layers. </li></ul>RPE UM <ul><li>There are 2 distinct type of melanocyte in the eye </li></ul>
  17. 18. - Melanocyte of the eye - <ul><li>Melanin has the ability to bind organic </li></ul><ul><li>amines and metal ions: this results in the </li></ul><ul><li>accumulation of these substances in the eye. </li></ul><ul><li>As an antioxidant, melanin protects eye cells </li></ul><ul><li>from chemical stress by binding ROS. </li></ul><ul><li>RPE plays a critical role in the metabolism of </li></ul><ul><li>retinoids, and in the active phagocytosis and </li></ul><ul><li>turnover of the rod outer segments of the </li></ul><ul><li>retina. </li></ul>Hu D-N, Savage HE. Uveal Melanocytes, Ocular Pigment Epithelium, and Müller Cells in Culture: In Vitro Toxicology Int J Toxicology 2002;21(6):465-472. Bok D. The retinal pigment epithelium: A versatile partner in vision. J Cell Sci Suppl 1993;17:189– 195. <ul><li>UM contain both eu- and pheomelanin, whereas RPE contains mainly eumelanin. </li></ul>RPE UM
  18. 19. - Melanocyte of the ear - <ul><li>COCHLEA </li></ul><ul><li>Melanocytes are present as intermediate cells in the stria vascularis of the cochlea. </li></ul><ul><li>Strial intermediate cells are required for the generation of endolymph-mediated </li></ul><ul><li>action potentials that are necessary for normal hearing. </li></ul><ul><li>Hearing impairment can be associated with inherited pigmentary disorders, e.g. </li></ul><ul><li>Waardenburg syndrome, and it has have shown that the extent of induce </li></ul><ul><li>temporary hearing loss is inversely related to skin pigment type. </li></ul><ul><li>Melanocyte are likely to contribute to the hearing process . </li></ul>Takeda K, Takahashi NH, Shibahara S. Neuroendocrine functions of melanocytes: Beyond the skindeep melanin maker. Tohoku J Exp Med 2007;211:201–221 . <ul><li>INNER EAR </li></ul><ul><li>Melanin granules produced by melanocytes in the inner ear play important roles in </li></ul><ul><li>balance . </li></ul>
  19. 20. <ul><li>Melanocytes have been identified in the brain and leptomeninges, and may have </li></ul><ul><li>many neuroendocrine functions. In particular: </li></ul><ul><li>- melanocyte are likely to contribute to sleeping regulation </li></ul><ul><li>- a melanocyte-derived factor might be involved in controlling the central </li></ul><ul><li>chemosensor that generates the respiratory rhythm. </li></ul><ul><li>Melanocyte of neural system produce neuromelanin, which has a protective </li></ul><ul><li>function by binding/removal of ROS and metals that are highly toxic to neurons. </li></ul>- Melanocyte of the brain - Takeda K, Takahashi NH, Shibahara S. Neuroendocrine functions of melanocytes: Beyond the skindeep melanin maker. Tohoku J Exp Med 2007;211:201–221. Zecca L, Bellei C, Costi P, et al. New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals. Proc Natl Acad Sci U S A 2008;105:17567–17572. Zucca FA, Giaveri G, Gallorini M, et al.The neuromelanin of human substantia nigra: Physiological and pathogenic aspects. Pigment Cell Res 2004;17:610–617.
  20. 21. - Melanocyte of the heart - <ul><li>Melanocytes have been identified in the valves and septa of the heart and their </li></ul><ul><li>numbers appear to reflect that of the skin. </li></ul><ul><li>Cardiac melanocytes depend on the same the signaling molecules that are crucial </li></ul><ul><li>for cutaneous melanocytes development, thus they may originate from the same </li></ul><ul><li>precursor population. </li></ul><ul><li>The function of cardiac melanocyte is still obscure. </li></ul><ul><li>It has been hypotesized that the dysfunction of melanocyte-like cells in the atrium </li></ul><ul><li>and in pulmonary venis may contribute to atrial arrhythmias. </li></ul><ul><li>Probably, cardiac melanocytes are not essential in a healthy and non-stressful </li></ul><ul><li>environment. </li></ul>Yajima I, Larue L. The location of heart melanocytes is specified and the level of pigmentation in the heart may correlate with coat color. Pigment Cell Melanoma Res 2008; 21:471–476. :471-476 . Brito FC, Kos L. Timeline and distribution of melanocyte precursors in the mouse heart. Pigment Cell Melanoma Res 2008;21:464–470. Levin MD, Lu MM, Petrenko NB, et al. Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers. J Clin Invest 2009; 119(11):3420-36. Shosuke Ito. Melanins seem to be everywhere in the body, but for what? Pig Cell & Mel Res 2009;22(1):12-13.
  21. 22. <ul><li>It has been recently demonstrated that melanin biosynthesis takes place in the </li></ul><ul><li>visceral adipose tissue of morbidly obese humans. </li></ul><ul><li>With the progression of obesity and the increase of cellular fat deposition, </li></ul><ul><li>adipocytes become more exposed to endogenous apoptotic signals, especially ROS. </li></ul><ul><li>The obese adipocytes ectopically may activate melanogenesis in order to neutralize </li></ul><ul><li>excess ROS and reduce oxidative damage. In addition, adipocytic melanin might </li></ul><ul><li>suppress the secretion of proinflammatory molecules. </li></ul><ul><li>It has been observed that fasting glucose levels correlated well to total outputs of </li></ul><ul><li>the melanogenic pathway in adipose tissues of obese patients. </li></ul>- Melanocyte of the adipose tissue - Randhawa M, Huff T, Valencia JC, et al. Evidence for the ectopic synthesis of melanin in human adipose tissue. FASEB J 2009; 23(3):835-843.
  22. 23. Summing up…. Locations and functions of melanocytes HAIR FOLLICLE Melanocyte stem cell reservoir for skin. Hair pigmentation, Removal of toxic byproducts EAR Inner ear : balance Cochlea : hearing EYE Choroid : Constitutive eye pigmentation, protection against UV Retinal pigment epithelium : vision, metabolism of rod outer segments and retinoids BRAIN Neuroendocrine function and detoxification HEART unknown ADIPOSE TISSUE Anti-inflammation, reduction/binding of ROS EPIDERMIS Constitutive skin pigmentation. Responses to and protection against the environment (primarily UV)
  23. 24. And also….
  24. 25. <ul><li>In lymphangioleiomyomatosis (LAM), muscle cells </li></ul><ul><li>revert towards their developmental origins and </li></ul><ul><li>express some melanocyte markers, such as tyrosinase, </li></ul><ul><li>Pmel17, gp100, etc.. </li></ul><ul><li>LAM cells can immunoreact with CD63, PNL2, both </li></ul><ul><li>markers for melanocyte differentiation. </li></ul><ul><li>Gp 100 expression suggests that a least some LAM </li></ul><ul><li>cells feature partial melanocytic differentiation. </li></ul>… . Melanocyte in the lung ?  LAM cells must be regarded as a fully abnormal type with the unique characteristic of having dual smooth cell/melanocyte differentiation.  This type of differentiation suggests a neural crest cell origin. Zhe X,Schuger L. Combined Smooth Muscle and Melanocytic Differentiation in Lymphangioleiomyomatosis. J Histochem Cytochem 2004;52(12):1537-1542. Ferrans VJ, Yu ZX, Nelson WK, et al. Lymphangioleiomyomatosis (LAM). a review of clinical and morphological features. J Nippon Med Sch 2000;67:311–329.
  25. 26. Melanocyte functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Reserve stem cell </li></ul><ul><li>Nervous system development </li></ul><ul><li>Tanning </li></ul><ul><li>Autocrine/paracrine function </li></ul>
  26. 27. <ul><li>Melanocytes are cells specialized in the synthesis of the pigment melanin </li></ul>Melanogenesis <ul><li>The name 'melanin' comes from the ancient Greek melanos , meaning 'dark', </li></ul><ul><li>and the term was probably first applied by the Swedish chemist Berzelius in 1840 </li></ul><ul><li>There are three types of melanin: </li></ul><ul><li>EUMELANIN </li></ul><ul><li>PHEOMELANIN </li></ul><ul><li>NEUROMELANIN </li></ul><ul><li>In addition to carotenoids and haemoglobin, melanin is the main </li></ul><ul><li>contributor to pigmentation of the skin, hair and eyes . </li></ul>
  27. 28. <ul><li>Eumelanin, the best-know form of melanin, exists in two forms: </li></ul><ul><li>Black melanin : produces black colours when it is present in large quantities, and </li></ul><ul><li>grey colours when it is rarer. It colours hair black, dark brown and grey. </li></ul><ul><li>Brown eumelanin : produces brown hair colours when it is present in abundance, </li></ul><ul><li>but smaller anmounts produce lighter brown or blond hair colours. </li></ul>EUMELANIN
  28. 29. <ul><li>Pheomelanin produces reddish colours of hair, eye and skin. </li></ul>PHEOMELANIN <ul><li>Pheomelanin is more abundant in </li></ul><ul><li>the skin of women than men and </li></ul><ul><li>their skin is slightly redder. </li></ul>
  29. 30. Eumelanin is a nitrogenous and insoluble pigment. Pheomelanin is a sulfur-containing and alkali-soluble pigment. EUMELANIN VS PHEOMELANIN Pheomelanin and eumelanin differ not only in colour but also in the size, shape and packaging of their granules.
  30. 31. <ul><li>Individual melanocyte can synthesize </li></ul><ul><li>both eu- and pheomelanin. </li></ul><ul><li>The synthesis of one the two </li></ul><ul><li>pigment is determined by a balance </li></ul><ul><li>of some variables, including: </li></ul><ul><li>- pigment enzyme expression </li></ul><ul><li>- availability of tyrosine and </li></ul><ul><li>sulphydryl-containing reducing </li></ul><ul><li>agents in the cell. </li></ul>EUMELANIN VS PHEOMELANIN <ul><li>The ratio of eu-/pheomelanin ranges from 1.31 to exclusively eumelanic. </li></ul><ul><li>Pheomelanin synthesis is characterized by the presence of spheroid melanosomes </li></ul><ul><li>whereas eumelanin synthesis is ascribed to ellipsoid melanosomes. </li></ul>Nakagawa H, Imokawa G. Characterization of melanogenesis in normal human epidermal melanocytes by chemical and ultrastructural analysis. Pigment Cell Res.1996;9(4):175-8.
  31. 32. Both melanins derive from a common tyrosinase-dependent pathway with the same precursor, tyrosine. The obligatory step is hydroxylation of tyrosine to dopaquinone, (DQ) from which L-DOPA can also be derived. From DQ, the two pathways diverge. EUMELANIN VS PHEOMELANIN Pheomelanin is derived from conjugation by thiol-containing cysteine or glutathione. It is more photolabile and can produce, among its by-products, hydrogen peroxide, superoxide and hydroxyl radicals. . Land, E. J. & Riley, P. A. Spontaneous redox reactions of dopaquinone and the balance between the eumelanic and phaeomelanic pathways. Pigment Cell Res 2000; 13, 273–277..
  32. 33. NEUROMELANIN <ul><li>Neuromelanin is the dark pigment that produces a black colour in certain parts of </li></ul><ul><li>the brain. </li></ul><ul><li>Neuromelanin is primarily localized in dopaminergic neurons of the substantia </li></ul><ul><li>nigra and in the locus coerulus , but virtually all brain tissue contain significant </li></ul><ul><li>amounts of neuromelanin. With age, it accumulates in the substantia nigra. </li></ul><ul><li>Neuromelanin consists of a large, complex, eumelanin- covered pheomelanin </li></ul><ul><li>core which may also contain aliphatics and peptides. </li></ul>Neurocuteneous melanosis. Boyd Smith A, Rushing E J, Smirniotopoulos JG. Pigmented Lesions of the Central Nervous System: Radiologic-Pathologic Correlation. Radiographics 2009;29:1503-1524 .
  33. 34. Melanocyte functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Tanning </li></ul>
  34. 35. <ul><li>Tanning results from a complex signalling pathway involving </li></ul><ul><li>keratinocytes and melanocytes . </li></ul><ul><li>It represents the physiological response of the epidermis to UV </li></ul><ul><li>radiation. </li></ul><ul><li>Tanning process can be divided in 4 phases: </li></ul><ul><li>1. Cytonkines production (KERATINOCYTE  MELANOCYTE) </li></ul><ul><li>2. Gene transcription (MELANOCYTE) </li></ul><ul><li>3. Pigment sinthesis (MELANOCYTE) </li></ul><ul><li>4. Melanin transfer (MELANOCYTE  KERATINOCYTE) </li></ul>Tanning
  35. 36. Miller AJ, Tsao H. New Insights into Pigmentary Pathways and Skin Cancer. The British Journal of Dermatology 2010;162(1):22-28. 1 2 3
  36. 37. <ul><li>Ultraviolet (UV) radiation reaching keratinocytes </li></ul><ul><li>leads to the production of a large number of </li></ul><ul><li>cytokines, including MSH (melanocyte </li></ul><ul><li>stimulationg factor). </li></ul><ul><li>CYTOKINES PRODUCTION </li></ul><ul><li>In the other cases, p53 triggers cell cycle arrest and </li></ul><ul><li>the expression of pro-piomelanocortin (POMC), </li></ul><ul><li>which is the precursor for α -MSH. </li></ul><ul><li>UV-induced photoproduct formation triggering a </li></ul><ul><li>repair response mediated by the xeroderma </li></ul><ul><li>pigmentosum (XP) DNA repair enzymes. </li></ul><ul><li>In cases of sever damage, p53 may induce apoptosis. </li></ul>
  37. 38. 2. GENE TRANSCRIPTION <ul><li>MSH secreted from keratinocytes binds to melanocortin-1 receptor (MC1R) on nearby melanocytes. </li></ul><ul><li>MSH binding promote MC1R transcription, the elevation of cAMP levels and then the expression of MITF (microphthalmia transcription factor ), that stimultes eumelanin production. </li></ul><ul><li>MSH and Agouti Signalling Peptide (ASIP) are both ligands which could bind to MC1R: MSH is an agonist, so promote MC1R transcription, while ASIP is an antagonist. </li></ul>
  38. 39. 3. PIGMENT SYNTHESIS <ul><li>Melanin production occurs predominantly in a </li></ul><ul><li>lysosome-like structure known as the melanosomes. </li></ul><ul><li>Melanin is packaged and delivered to keratinocytes </li></ul><ul><li>by melanosomes. The formation, maturation and </li></ul><ul><li>trafficking of melanosomes is crucial to pigmentation, </li></ul>
  39. 40. Sinthesis passages of eu- and pheomelanin from tyrosine
  40. 41. Melanosomes are formed from two sources: - In the Smooth Endoplasmic Reticulum (SER), pre-melanosomes are produced by coalescence of vesicles, and appear to contain parallel filamentous contents. - In the Rough Endoplasmic Reticulum (RER) and Golgi complex, tyrosinase and other enzymes are synthesised and packaged into vesicles. Melanosomes synthesis These fuse with the pre-melanosomes.
  41. 42. Localization of melanogenesis phases within the melanocyte <ul><li>Stage I to IV melanosomes are formed in cytosol and distributed long the dendritic prolongation . </li></ul><ul><li>The structural proteins of melanosomes and tyrosinase and are synthesized on ribosomes associated with RER </li></ul><ul><li>In the Golgi, these are packaged in small vesicles which elongate as the lamellar framework of the melanosome is assembled. </li></ul>
  42. 43. Post-Golgi transport of melanosomes in melanocyte citosol
  43. 44. <ul><li>On the keratinocyte side, the protease- activated receptor-2 (PAR2), a seven-transmembrane receptor on keratinocytes, has a central role in melanosome transfer . </li></ul><ul><li>Melanosomes are tranferred to keratinocytes trough dendrites </li></ul>4. MELANIN TRANSFER
  44. 45. Once in keratinocytes, melanosomes are distributed and -in response to UVR- positioned strategically over the ‘sun-exposed’ side of nuclei, to form cap-like structures resembling umbrellas.
  45. 46. Melanocyte functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Autocrine/paracrine function </li></ul><ul><li>Tanning </li></ul>
  46. 47. Summary of the major participants in the paracrine/autocrine network that regulates melanocyte functions and survival.
  47. 48. Factors of the paracrine/autocrine network that regulates melanocyte functions, proliferation and survival, with their cellular origin, role in pigmentation and effects on melanocytes Abdel-Malek ZA, Swope VB. Epidermal melanocytes: regulation of their survivial, proliferation and function in human skin. In: Melanoma Development: Molecular Biology, Genetics and Clinical Application. A Bosserhoff ed. Springer-Verlag, Wien 2011. p.11.
  48. 49. Key molecules and signaling pathways implicated in melanocyte-keratinocyte interactions
  49. 50. Role of ET-1 and melanocortins in the DNA Damage Response Abdel-Malek ZA, Swope VB. Epidermal melanocytes: regulation of their survivial, proliferation and function in human skin. In: Melanoma Development: Molecular Biology, Genetics and Clinical Application. A Bosserhoff ed. Springer-Verlag, Wien 2011. p.22. ET-1 : endothelin-1; ETBR :endothelin-1 B receptor , MC1R : melanocortin-1 receptor
  50. 51. Tsatmali M, Ancas J, Thody JA. Melanocyte functions and its control by melanocortin peptides. J Histoc & Cytochemistry 2002; 50(2):125-133. Effects of melanocortins (MSH and ACTH) stimulation on melanocyte in response to environmental stress
  51. 52. Corticotropin Releasing Hormon central role in the skin response to stress Slominski A, Wortsman J, Pisarchik A, et al. Cutaneous expression of corticotropin-releasing hormone (CRH), urocortin, and CRH receptors . The FASEB Journal. 2001;15:1678-1693
  52. 53. <ul><li>Human melanocytes express FP receptor (the receptor for PGF2 α ) in vitro and in vivo, and expression of this receptor was upregulated upon UV exposure </li></ul>Eicosanoids as Paracrine/Autocrine factors for Melanocytes Starner RJ, McClelland L, Abdel-Malek Z, et al.PGE(2) is a UVR-inducible autocrine factor for human melanocytes that stimulates tyrosinase activation. Exp Dermatol 2010;19:682–684 <ul><li>Melanocytes respond to PGF2 α with stimulation of dendricity, and melanogenesis that is evidenced by increased activity and protein levels of tyrosinase. </li></ul><ul><li>The leukotrienes LTC4 and D4 were found to be potent mitogens for cultured human melanocytes </li></ul>Morelli JG, Yohn JJ, Lyons MB, et al. Leukotrienes C4 and D4 as potent mitogens for cultured human melanocytes. J Investig Dermatol 1989;93:719–722
  53. 54. Melanocyte functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Tanning </li></ul><ul><li>Autocrine/paracrine function </li></ul><ul><li>Reserve stem cells </li></ul>
  54. 55. Melanocyte of the hair follicle <ul><li>Melanocyte Stem Cell ( MSCs ) and hair follicle stem cells (SCs) reside in a common niche within the permanent portion of the hair follicle (HF), the bulge . </li></ul><ul><li>Progressive loss of MSCs determine hair </li></ul><ul><li>graying in both humans and mice. </li></ul><ul><li>TGF- β produced in this specialized niche regulates the function of MSCs in the HF. </li></ul>Nishimura EK, Suzuki M, Igras V, et al. Key roles for transforming grow factor- β in melanocyte stem cell mainteinance. Cell Stem Cell 2010; 6:130-140.
  55. 56. <ul><li>In catagen , all cells of the lower HF, including the mature melanocytes and rapidly cycling transit-amplifying (TA) matrix cells, die by apoptosis, except MSCs and SCs. </li></ul><ul><li>During anagen , MSCs and SCs proliferate, migrate downwards, and give rise to TA matrix cells and TA melanocytes that differentiate to produce the colored hair shaft. </li></ul>Melanocyte of the hair follicle Nishimura EK, Suzuki M, Igras V, et al. Key roles for transforming grow factor- β in melanocyte stem cell mainteinance. Cell Stem Cell 2010; 6:130-140.
  56. 57. Melanocyte functions <ul><li>Sinthesis of melanins (melanogenesis) </li></ul><ul><li>Reserve stem cells </li></ul><ul><li>Nervous system development </li></ul><ul><li>Tanning </li></ul><ul><li>Autocrine/paracrine function </li></ul>
  57. 58. <ul><li>Melanocytes and melanin play critical roles during embryonic development. </li></ul><ul><li>This can be seen in individuals with oculocutaneous albinism type 1 (OCA1). OCA1 results from the dysfunction of TYR which leads to impaired pigmentation of skin, hair and eyes but also to misrouting of the optic nerves at the chiasm. </li></ul>King, RA; Hearing, VJ.; Creel, DJ., et al. Albinism. In: Scriver, CR.; Beaudet, AL.; Sly, WS.; Valle, D., editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill 2001. p. 5587-5627. Le, Pape E.; Passeron, T.; Giubellino, A.; et al. Microarray analysis reveals the complex effects of MC1R signaling in melanocytes. Proc Natl Acad Sci U S A. 2009 ; 10;106(6):1802-7. Nervous system development <ul><li>The antagonist agouti signaling protein (ASP) was shown recently to modulate the expression of genes involved in morphogenesis, especially in nervous system development. </li></ul>
  58. 59. <ul><li>Melanocytes are not simply melanin-producing cells, but have several </li></ul><ul><li>functions </li></ul><ul><li>Besides the skin, melanocyte reside in multiple tissues of the body </li></ul><ul><li>They are capable of secreting a wide range of signaling molecules, within </li></ul><ul><li>the paracrine/autocrine network of the skin. </li></ul><ul><li>Melanocytes are likely to function as regulator cells in mantaining </li></ul><ul><li>epidermal homeostasis. </li></ul>Conclusions
  59. 60. Co-culture of human epidermal keratinocytes (red) and melanocytes (green), showing melanosome transfer into keratinocytes with DNA counterstaining (blue).
  60. 61. … for your attention. yo for your for attention…. Thank you… www.torellolotti.it professor @ torellolotti.it

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