RESUMO
BACKGROUND: Aging and aging-related disorders impair the survival and differentiation potential of bone marrow mesenchymal stem cells (MSCs) and limit their therapeutic efficacy. Induced pluripotent stem cells (iPSCs) may provide an alternative source of functional MSCs for tissue repair. This study aimed to generate and characterize human iPSC-derived MSCs and to investigate their biological function for the treatment of limb ischemia. METHODS AND RESULTS: Human iPSCs were induced to MSC differentiation with a clinically compliant protocol. Three monoclonal, karyotypically stable, and functional MSC-like cultures were successfully isolated using a combination of CD24(-) and CD105(+) sorting. They did not express pluripotent-associated markers but displayed MSC surface antigens and differentiated into adipocytes, osteocytes, and chondrocytes. Transplanting iPSC-MSCs into mice significantly attenuated severe hind-limb ischemia and promoted vascular and muscle regeneration. The benefits of iPSC-MSCs on limb ischemia were superior to those of adult bone marrow MSCs. The greater potential of iPSC-MSCs may be attributable to their superior survival and engraftment after transplantation to induce vascular and muscle regeneration via direct de novo differentiation and paracrine mechanisms. CONCLUSIONS: Functional MSCs can be clonally generated, beginning at a single-cell level, from human iPSCs. Patient-specific iPSC-MSCs can be prepared as an "off-the-shelf" format for the treatment of tissue ischemia.
Assuntos
Membro Posterior/irrigação sanguínea , Isquemia/cirurgia , Células-Tronco Mesenquimais/fisiologia , Células-Tronco Pluripotentes/citologia , Adipócitos/citologia , Animais , Diferenciação Celular , Linhagem Celular , Condrócitos/citologia , Células Clonais/transplante , Células Endoteliais/citologia , Fibroblastos/citologia , Vetores Genéticos/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Camundongos , Camundongos SCID , Miócitos de Músculo Liso/citologia , Osteócitos/citologia , Comunicação Parácrina , Células-Tronco Pluripotentes/transplante , Proteínas Recombinantes de Fusão/fisiologia , Recuperação de Função Fisiológica , Teratoma/patologia , Transdução Genética , Transplante HeterólogoRESUMO
This retrospective study included 23 necrotic immature permanent teeth treated for either short-term (treatment period <3 months) or long-term (treatment period >3 months) using conservative endodontic procedures with 2.5% NaOCl irrigations without instrumentation but with Ca(OH)(2) paste medication. For seven teeth treated short-term, the gutta-percha points were filled onto an artificial barrier of mineral trioxide aggregate (MTA). For 16 teeth treated long-term, the gutta-percha points, amalgam, or MTA were filled onto the Ca(OH)(2)-induced hard tissue barrier in the root canal. We found that all apical lesions showed complete regression in 3 to 21 (mean, 8) months after initial treatment. All necrotic immature permanent teeth achieved a nearly normal root development 10 to 29 (mean, 16) months after initial treatment. We conclude that immature permanent teeth with pulp necrosis and apical pathosis can still achieve continued root development after proper short-term or long-term regenerative endodontic treatment procedures.
