Fibronectin and laminin promote differentiation of human mesenchymal stem cells into insulin producing cells through activating Akt and ERK

Abstract

BackgroundIslet transplantation provides a promising cure for Type 1 diabetes; however it is limited by a shortage of pancreas donors. Bone marrow-derived multipotent mesenchymal stem cells (MSCs) offer renewable cells for generating insulin-producing cells (IPCs).MethodsWe used a four-stage differentiation protocol, containing neuronal differentiation and IPC-conversion stages, and combined with pellet suspension culture to induce IPC differentiation.ResultsHere, we report adding extracellular matrix proteins (ECM) such as fibronectin (FN) or laminin (LAM) enhances pancreatic differentiation with increases in insulin and Glut2 gene expressions, proinsulin and insulin protein levels, and insulin release in response to elevated glucose concentration. Adding FN or LAM induced activation of Akt and ERK. Blocking Akt or ERK by adding LY294002 (PI3K specific inhibitor), PD98059 (MEK specific inhibitor) or knocking down Akt or ERK failed to abrogate FN or LAM-induced enhancement of IPC differentiation. Only blocking both of Akt and ERK or knocking down Akt and ERK inhibited the enhancement of IPC differentiation by adding ECM.ConclusionsThese data prove IPC differentiation by MSCs can be modulated by adding ECM, and these stimulatory effects were mediated through activation of Akt and ERK pathways.

Differentiation of Stem Cells into Insulin-Producing Cells: Current Status and Challenges

“…Many types of differentiation protocols have been developed, which ultimately led to achieve the desired results confirming the presented theory (Gao et al 2008;Lin et al 2010;Oh et al 2004). …”

“…These proteins enhanced pancreatic differentiation from MSCs: stimulated insulin and GLUT2 gene expressions, increased proinsulin and insulin protein levels. Moreover they enhanced insulin secretion in response to glucose stimulation and accumulation of insulin granules in IPCs (Table 3) (Lin et al 2010). Gao et al (2008) have indicated that extracellular matrix gel plays an important role not only in differentiation of human umbilical cord blood derived MSCs into IPCs, but also in maturation and formation of three dimensional structures.…”

THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away

“…Other in vitro murine studies have shown that BM mesenchymal stem cells (MSCs) can be directly differentiated into insulin producing cells capable of reversing hyperglycemia after transplantation in diabetic animals (49,50). In vitro generation of insulin producing cells from human BM and umbilical cord MSCs have also been reported (51,52). However, the functionality and glucose responsiveness of these cells are unclear.…”

A Short-activating RNA Oligonucleotide Targeting the Islet β-cell Transcriptional Factor MafA in CD34+ Cells

“…23 More recently, targeted activation of crucial pancreatic transcription factors successfully generated insulin-secreting cells; 24,25,26,27 however, because these methods depend largely on the use of lentiviral vectors, their potential for clinical use is restrained. 28,29,30,31 …”