Regeneration of the entire human epidermis using transgenic stem cells

被引：501

作者：

Hirsch, Tobias ^{[1
]}

Rothoeft, Tobias ^{[2
]}

Teig, Norbert ^{[2
]}

Bauer, Johann W. ^{[3
]}

Pellegrini, Graziella ^{[4
,5
]}

De Rosa, Laura ^{[5
]}

Scaglione, Davide ^{[6
]}

Reichelt, Julia ^{[3
]}

Klausegger, Alfred ^{[3
]}

Kneisz, Daniela ^{[3
]}

Romano, Oriana ^{[7
]}

Seconetti, Alessia Secone ^{[5
]}

Contin, Roberta ^{[5
]}

Enzo, Elena ^{[5
]}

Jurman, Irena ^{[8
,9
]}

Carulli, Sonia ^{[10
]}

Jacobsen, Frank

Luecke, Thomas ^{[11
]}

Lehnhardt, Marcus ^{[1
]}

Fischer, Meike ^{[2
]}

Kueckelhaus, Maximilian ^{[1
]}

Quaglino, Daniela ^{[7
]}

Morgante, Michele ^{[8
,9
]}

Bicciato, Silvio ^{[7
]}

Bondanza, Sergio ^{[10
]}

De Luca, Michele ^{[5
]}

机构：

[1] Ruhr Univ Bochum, BG Univ Hosp Bergmannsheil, Burn Ctr, Dept Plast Surg, D-44789 Bochum, Germany

[2] Ruhr Univ Bochum, Univ Childrens Hosp, Dept Neonatol & Pediat Intens Care, D-44791 Bochum, Germany

[3] Paracelsus Med Univ, Univ Hosp, EB House Austria & Dept Dermatol, A-5020 Salzburg, Austria

[4] Univ Modena & Reggio Emilia, Dept Surg Med Dent & Morphol Sci, I-41124 Modena, Italy

[5] Univ Modena & Reggio Emilia, Dept Life Sci, Ctr Regenerat Med Stefano Ferrari, I-41125 Modena, Italy

[6] IGA Technol Serv Srl, I-33100 Udine, Italy

[7] Univ Modena & Reggio Emilia, Dept Life Sci, I-41125 Modena, Italy

[8] Univ Udine, Ist Genom Appl, I-33100 Udine, Italy

[9] Univ Udine, Dipartimento Sci Agroalimentari Ambientail & Anim, I-33100 Udine, Italy

[10] Holostem Terapie Avanzate Srl, I-41125 Modena, Italy

[11] Ruhr Univ Bochum, Univ Childrens Hosp, Dept Neuropediat, D-44791 Bochum, Germany

来源：

NATURE | 2017年 / 551卷 / 7680期

基金：

欧洲研究理事会;

关键词：

GENE-THERAPY; EPIDERMOLYSIS-BULLOSA; CLONAL ANALYSIS; TRANSPLANTATION; BURNS; KERATINOCYTE; PACKAGE; CANCER; SAFETY;

D O I：

10.1038/nature24487

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：327 / +

页数：20

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