Melinda Snitow

Type 1 diabetes (T1D) is the result of an autoimmune destruction of pancreatic beta cells. The cellular and molecular defects that cause the disease remain unknown. Pluripotent cells generated from patients with T1D would be useful for disease modeling. We show here that induced pluripotent stem (iPS) cells can be generated from patients with T1D by reprogramming their adult fibroblasts with three transcription factors (OCT4, SOX2, KLF4). T1D-specific iPS cells, termed DiPS cells, have the hallmarks of pluripotency and can be differentiated into insulin-producing cells. These results are a step toward using DiPS cells in T1D disease modeling, as well as for cell replacement therapy.

In contrast to lower vertebrates, the mammalian heart has limited capacity to regenerate after injury in part due to ineffective reactivation of cardiomyocyte proliferation. We show that the microRNA cluster miR302-367 is important for cardiomyocyte proliferation during development and is sufficient to induce cardiomyocyte proliferation in the adult and promote cardiac regeneration. In mice, loss of miR302-367 led to decreased cardiomyocyte proliferation during development. In contrast, increased miR302-367 expression led to a profound increase in cardiomyocyte proliferation, in part through repression of the Hippo signal transduction pathway. Postnatal reexpression of miR302-367 reactivated the cell cycle in cardiomyocytes, resulting in reduced scar formation after experimental myocardial infarction. However, long-term expression of miR302-367 induced cardiomyocyte dedifferentiation and dysfunction, suggesting that persistent reactivation of the cell cycle in postnatal cardiomyocytes is not desirable. This limitation can be overcome by transient systemic application of miR302-367 mimics, leading to increased cardiomyocyte proliferation and mass, decreased fibrosis, and improved function after injury. Our data demonstrate the ability of microRNA-based therapeutic approaches to promote mammalian cardiac repair and regeneration through the transient activation of cardiomyocyte proliferation.