Fully functional hair follicle regeneration through the rearrangement of stem cells and their niches. Organ replacement regenerative therapy is purported to enable the replacement of organs damaged by disease, injury or aging in the foreseeable future. Here we demonstrate fully functional hair organ regeneration via the intracutaneous transplantation of a bioengineered pelage and vibrissa follicle germ. The pelage and vibrissae are reconstituted with embryonic skin-derived cells and adult vibrissa stem cell region-derived cells, respectively. The bioengineered hair follicle develops the correct structures and forms proper connections with surrounding host tissues such as the epidermis, arrector pili muscle and nerve fibres. The bioengineered follicles also show restored hair cycles and piloerection through the rearrangement of follicular stem cells and their niches. This study thus reveals the potential applications of adult tissue-derived follicular stem cells as a bioengineered organ replacement therapy. Organ replacement regenerative therapy is expected to provide novel therapeutic systems for donor organ transplantation, which is an approach to treating patients who experience organ dysfunction as the result of disease, injury or aging1. Concepts in current regenerative therapy include stem cell transplantation and two-dimensional uniform cell sheet technologies, both of which have the potential to restore partially lost tissue or organ function. The
development of bioengineered ectodermal organs, such as teeth, salivary glands, or hair follicles may be achieved by reproducing the developmental processes that occur during organogenesis. Ectodermal organs have essential physiological roles and can greatly influence the quality of life by preventing the morbidity associated with afflictions such as caries and hypodontia in teeth10, hyposalivation in the salivary gland, and androgenetic alopecia, which affects the hair12. Recently, it has been proposed that a bioengineered tooth can restore oral and physiological function through the transplantation of bioengineered tooth germ and a bioengineered mature tooth unit, which would represent a successful organ-replacement regenerative therapy.The hair coat has important roles in thermoregulation, physical insulation, sensitivity to noxious stimuli, and social communication. In the developing embryo, hair follicle morphogenesis is regulated by reciprocal epithelial and mesenchymal interactions that occur in almost all organs. The hair follicle is divided into a permanent upper region, which consists of the infundibulum and isthmus, and a variable lower region, which is the actual hair-shaft factory that contains the hair matrix, differentiated epithelial cells and dermal papilla (DP) cells. DP cells are responsible for the production of dermal-cell populations such as
dermal sheath (DS) cells, and they generate dermal fibroblasts and adipocytes. After morphogenesis, various stem cell types are maintained in certain regions of the follicle. For instance, follicle epithelial cells are found in the follicle stem cell niche of the bulge region; multipotent mesenchymal precursors are found in DP cells; neural crest-derived melanocyte progenitors are located in the sub-bulge region, and follicle epithelial stem cells in the bulge region that is connected to the arrector pili muscle. The follicle variable region mediates the hair cycle, which depends on the activation of follicle epithelial stem cells in the bulge stem cell niche during the telogen-to-anagen transition. This transition includes phases of growth (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen), whereas the organogenesis of most organs is induced only once during embryogenesis.To achieve hair follicle regeneration in the hair cycle, it is thought to be essential to regenerate the various stem cells and their niches. Many studies have attempted to develop technologies to renew the variable lower region of the hair follicle, to achieve de novo folliculogenesis via replacement with hair follicle-inductive dermal cells, and to direct the self-assembly of skin-derived
epithelial and mesenchymal cells. We have also reported that a bioengineered hair follicle germ, reconstituted from embryonic follicle germ-derived epithelial and mesenchymal cells, using our organ germ method, can generate a bioengineered hair follicle and shaft7. However, it remains to be determined whether the bioengineered hair follicle germ can generate a bioengineered hair follicle and shaft by intracutaneous transplantation to provide fully functional hair regeneration, including hair shaft elongation, hair cycles, connections with surrounding tissues, and the regeneration of stem cells and their niches. Here we demonstrate fully functional orthotopic hair regeneration via the intracutaneous transplantation of bioengineered hair follicle germ. The bioengineered hair has the correct structures of the naturally occurring hair follicle and shaft, and it forms proper connections with surrounding host tissues, such as the epidermis, arrector pili muscle and nerve fibres. The bioengineered hair follicles show full functionality, including the ability to undergo repeated hair cycles through the rearrangement of various stem cell niches, as well as responsiveness to the neurotransmitter acetylcholine (ACh). Our current study thus demonstrates the potential for not only hair regeneration therapy but also the realization of bioengineered organ replacement using adult somatic stem cells. Sources: Nature Publishing Group & Tokyo University of Science, Japan.
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