Synthetic Developmental Tissue Engineering of Human Hair Follicles

项目摘要 人类皮肤等效物（HSE）已经为由于以下原因而具有显著皮肤损失的患者提供了有效的治疗： 烧伤、溃疡和遗传性皮肤病;然而，它们仍然具有各种局限性，包括生存能力差， 缺少附属物或毛发密度不匹配。我们最近通过以下方法提高了皮肤移植物的存活率： 建立了一种方法来对HSE中的脉管系统进行微图案化。另一方面，它仍然是一个普遍的 长期培养人毛乳头后毛囊移植对功能性皮肤的挑战 细胞（DPC）在体外失去它们的毛发诱导能力。该项目的总体目标是设计可行的， 使用培养的人类细胞制造具有附属物的功能性皮肤等同物。我们将采用生物工程， 用遗传学和系统生物学方法将培养的DPC和真皮成纤维细胞重编程为毛发 感应细胞然后，这些细胞将用于生成带有毛发的3D皮肤等效物， 为严重皮肤/脱发患者开发真正功能性皮肤替代品。特别是要 使用i）微制造技术来重现3D毛囊微环境（微环境 方法）和ii）反向工程基因网络分析以重新编程毛发诱导基因标签， 培养的DPC和成纤维细胞（遗传方法）。最后，利用我们最近建立的 血管化技术，我们将开发可行的HSE，在移植后，可以可控地再生 头发和保持完全整合，由于加强血管重建。再生整根头发的能力 来自培养的人类细胞的卵泡将对医学管理产生压倒性的积极影响。 不同类型的脱发、大疱性表皮病以及慢性伤口、严重感染和烧伤， 其中主要是未满足的医疗需求。生成毛发皮肤的能力是关键的一步 这将标志着再生医学在概念上的巨大进步， 医学方法的皮肤和毛囊疾病，如脱发，以及改善 严重皮肤损伤导致毁容疤痕的结果。

Project Summary Human skin equivalents (HSEs) have provided an effective therapy for patients with significant skin loss due to burns, ulcers and genetic skin diseases; however they still have various limitations including poor viability and lack of appendages or mismatch in hair density. We have recently improved the viability of skin grafts by establishing a method to micropattern vasculature in HSEs. On the other hand, it still remains a prevailing challenge to engineer functional skin grafts with hair follicles since long-term cultured human dermal papilla cells (DPCs) in vitro lose their hair-inducing capacity. The overall goal of this project is to engineer viable and functional skin equivalents with appendages using cultured human cells. We will employ bioengineering, genetics and systems biology approaches to reprogram cultured DPCs and dermal fibroblasts into hair inductive cells. These cells will then be used to generate hair-bearing 3D skin equivalents, enabling the development of truly functional skin substitutes for patients with significant skin/hair loss. In particular, we will use i) microfabrication techniques to recapitulate 3D hair follicle microenvironment (microenvironmental approach) and ii) reverse engineering gene network analysis to reprogram hair inductive gene signatures of cultured DPCs and fibroblasts (genetic approach). Finally, taking advantage of our recently established technique for vascularization, we will develop viable HSEs that, after engraftment, can controllably regenerate hair and remain fully integrated due to enhanced revascularization. The ability to regenerate an entire hair follicle from cultured human cells will have an overwhelming positive impact on the medical management of different types of alopecia, epidermolysis bullosa as well as chronic wounds, severe infections, and burns, all of which represent major unmet medical needs. The ability to generate a hair-bearing skin is a crucial step towards making a truly functional human skin and would mark a dramatic conceptual advance in regenerative medicine approaches to disorders of the skin and hair follicle, such as hair loss, as well as improve the outcome of severe skin injuries leading to disfiguring scars.