Islet transplantation is considered as an ultimate option for the treatment of 
type I diabetes. Human induced pluripotent stem cells (hiPSCs) have raised the 
possibility that patient-specific insulin-secreting cells might be derived from 
somatic cells through cell fate reprogramming. However, current protocols mostly 
rely on the use of several cytokines and inhibitors for directing 
differentiation towards pancreatic fate. Given the high manufacturing cost of 
these recombinant proteins, this approach is prohibitive for clinical 
applications. Knowing that microRNAs (miRNAs) are key players in various stages 
of pancreatic development, we present a novel and cost-effective strategy in 
which over-expression of miR-375 promotes pancreatic differentiation in hiPSCs 
in the absence of any other stimulator. We used a polycistronic viral vector 
expressing Sox2, Klf4, c-Myc, and Oct4 to drive hiPSCs from human foreskin 
fibroblasts. The established hiPSCs are similar to human embryonic stem cells in 
many aspects including morphology, passaging, surface and pluripotency markers, 
and gene expression. For differentiation induction, miR-375 was lentivirally 
overexpressed in these hiPSCs. Morphological assessment, immunocytochemistry, 
and expression analysis of islet marker genes confirmed that islet like cells 
were obtained in miR-375 transduced cells compared to controls. Our 
differentiated clusters secreted insulin in a glucose-dependant manner, showing 
in vitro functionality. We demonstrated for the first time that miRNAs might be 
ideal substitutes to induce pancreatic differentiation in hiPSCs. This work 
provides a new approach to study the role of miRNAs in pancreatic specification 
and increase the feasibility of using patient-specific iPSCs for beta cell 
replacement therapy for type I diabetes.