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Regeneration of the entire human epidermis using transgenic stem cells.

ABSTRACT: Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. The proviral integration pattern was maintained in vivo and epidermal renewal did not cause any clonal selection. Clonal tracing showed that the human epidermis is sustained not by equipotent progenitors, but by a limited number of long-lived stem cells, detected as holoclones, that can extensively self-renew in vitro and in vivo and produce progenitors that replenish terminally differentiated keratinocytes. This study provides a blueprint that can be applied to other stem cell-mediated combined ex vivo cell and gene therapies.

SUBMITTER: Hirsch T

PROVIDER: S-EPMC6283270 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Regeneration of the entire human epidermis using transgenic stem cells.

Hirsch Tobias T Rothoeft Tobias T Teig Norbert N Bauer Johann W JW Pellegrini Graziella G De Rosa Laura L Scaglione Davide D Reichelt Julia J Klausegger Alfred A Kneisz Daniela D Romano Oriana O Secone Seconetti Alessia A Contin Roberta R Enzo Elena E Jurman Irena I Carulli Sonia S Jacobsen Frank F Luecke Thomas T Lehnhardt Marcus M Fischer Meike M Kueckelhaus Maximilian M Quaglino Daniela D Morgante Michele M Bicciato Silvio S Bondanza Sergio S De Luca Michele M

Nature 20171108 7680

Junctional epidermolysis bullosa (JEB) is a severe and often lethal genetic disease caused by mutations in genes encoding the basement membrane component laminin-332. Surviving patients with JEB develop chronic wounds to the skin and mucosa, which impair their quality of life and lead to skin cancer. Here we show that autologous transgenic keratinocyte cultures regenerated an entire, fully functional epidermis on a seven-year-old child suffering from a devastating, life-threatening form of JEB. ...[more]

PMID: 29144448

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Project description:Cleft lip and palate is a congenital disorder including cleft lip, and/or cleft palate, and/or alveolar cleft, with high incidence.The alveolar cleft causes morphological and functional abnormalities. To obtain bone bridge formation and continuous structure between alveolar clefts, surgical interventions are performed from infancy to childhood. However, desirable bone bridge formation is not obtained in many cases. Regenerative medicine using mesenchymal stem cells (MSCs) is expected to be a useful strategy to obtain sufficient bone bridge formation between alveolar clefts. In this study, we examined the effect of human umbilical cord-derived MSCs by transplantation into a rat experimental alveolar cleft model. Human umbilical cords were digested enzymatically and the isolated cells were collected (UC-EZ cells). Next, CD146-positive cells were enriched from UC-EZ cells by magnetic-activated cell sorting (UC-MACS cells). UC-EZ and UC-MACS cells showed MSC gene/protein expression, in vitro. Both cells had multipotency and could differentiate to osteogenic, chondrogenic, and adipogenic lineages under the differentiation-inducing media. However, UC-EZ cells lacked Sox2 expression and showed the lower ratio of MSCs than UC-MACS cells. Thus, UC-MACS cells were transplanted with hydroxyapatite and collagen (HA + Col) into alveolar cleft model to evaluate bone formation in vivo. The results of micro computed tomography and histological staining showed that UC-MACS cells with HA + Col induced more abundant bone formation between the experimental alveolar clefts than HA + Col implantation only. Cells immunopositive for osteopontin were accumulated along the bone surface and some of them were embedded in the bone. Cells immunopositive for human-specific mitochondria were aligned along the newly formed bone surface and in the new bone, suggesting that UC-MACS cells contributed to the bone bridge formation between alveolar clefts. These findings indicate that human umbilical cords are reliable bioresource and UC-MACS cells are useful for the alveolar cleft regeneration.

Dataset Information

Regeneration of the entire human epidermis using transgenic stem cells.

Publications

Regeneration of the entire human epidermis using transgenic stem cells.

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