• 来稿:陈琳   北京市虹天济神经科学研究院

  • Philos Trans R  Soc Lond B Biol Sci. 2004 May 29;359(1445):839-50. 

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  • Scar-free healing: from embryonic mechanisms to adult  therapeutic intervention

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  • Ferguson  MW, O'Kane S.

  • UK Centre for Tissue Engineering, School of Biological  Sciences, University of Manchester, 3.239 Stopford Building, Oxford Road,  Manchester M13 9PT, UK. mark.ferguson@man.ac.uk   

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  • In man and domestic animals, scarring in the skin after  trauma, surgery, burn or sports injury is a major medical problem, often  resulting in adverse aesthetics, loss of function, restriction of tissue  movement and/or growth and adverse psychological effects. Current treatments are  empirical, unreliable and unpredictable: there are no prescription drugs for the  prevention or treatment of dermal scarring. Skin wounds on early mammalian  embryos heal perfectly with no scars whereas wounds to adult mammals scar. We  investigated the cellular and molecular differences between scar-free healing in  embryonic wounds and scar-forming healing in adult wounds. Important differences  include the inflammatory response, which in embryonic wounds consists of lower  numbers of less differentiated inflammatory cells. This, together with high  levels of morphogenetic molecules involved in skin growth and morphogenesis,  means that the growth factor profile in a healing embryonic wound is very  different from that in an adult wound. Thus, embryonic wounds that heal without  a scar have low levels of TGFbeta1 and TGFbeta2, low levels of platelet-derived  growth factor and high levels of TGFbeta3. We have experimentally manipulated  healing adult wounds in mice, rats and pigs to mimic the scar-free embryonic  profile, e.g. neutralizing PDGF, neutralizing TGFbeta1 and TGFbeta2 or adding  exogenous TGFbeta3. These experiments result in scar-free wound healing in the  adult. Such experiments have allowed the identification of therapeutic targets  to which we have developed novel pharmaceutical molecules, which markedly  improve or completely prevent scarring during adult wound healing in  experimental animals. Some of these new drugs have successfully completed safety  and other studies, such that they have entered human clinical trials with  approval from the appropriate regulatory authorities. Initial trials involve  application of the drug or placebo in a double-blind randomized design, to  experimental incision or punch biopsy wounds under the arms of human volunteers.  Based on encouraging results from such human volunteer studies, the lead drugs  have now entered human patient-based trials e.g. in skin graft donor sites. We  consider the evolutionary context of wound healing, scarring and regeneration.  We hypothesize that evolutionary pressures have been exerted on intermediate  sized, widespread, dirty wounds with considerable tissue damage e.g. bites,  bruises and contusions. Modem wounds (e.g. resulting from trauma or surgery)  caused by sharp objects and healing in a clean or sterile environment with close  tissue apposition are new occurrences, not previously encountered in nature and  to which the evolutionary selected wound healing responses are somewhat  inappropriate. We also demonstrate that both repair with scarring and  regeneration can occur within the same animal, including man, and indeed within  the same tissue, thereby suggesting that they share similar mechanisms and  regulators. Consequently, by subtly altering the ratio of growth factors present  during adult wound healing, we can induce adult wounds to heal perfectly with no  scars, with accelerated healing and with no adverse effects, e.g. on wound  strength or wound infection rates. This means that scarring may no longer be an  inevitable consequence of modem injury or surgery and that a completely new  pharmaceutical approach to the prevention of human scarring is now possible.  Scarring after injury occurs in many tissues in addition to the skin. Thus  scar-improving drugs could have widespread benefits and prevent complications in  several tissues, e.g. prevention of blindness after scarring due to eye injury,  facilitation of neuronal reconnections in the central and peripheral nervous  system by the elimination of glial scarring, restitution of normal gut and  reproductive function by preventing strictures and adhesions after injury to the  gastrointestinal or reproductive systems, and restoration of locomotor function  by preventing scarring in tendons and ligaments.

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神经疾病的细胞疗法:基础研究指导临床应用,临床应用升华基础研究
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无瘢痕愈合:从胚胎机制到成人治疗干预策略