Pdx1-transfected adipose tissue-derived stem cells differentiate into insulin-producing cells in vivo and reduce hyperglycemia in diabetic mice

Abstract

Insulin-dependent diabetes mellitus (IDDM) is characterized by the rapid development of potentially severe metabolic abnormalities resulting from insulin deficiency. The transplantation of insulin-producing cells is a promising approach for the treatment of IDDM. The transcription factor pancreatic duodenal homeobox 1 (Pdx1) plays an important role in the differentiation of pancreatic beta cells. In this study, the human Pdx1 gene was transduced and expressed in murine adipose tissue-derived stem cells (ASCs). To evaluate pancreatic repair, we used a mouse model of pancreatic damage resulting in hyperglycemia, which involves injection of mice with streptozotocin (STZ). STZ-treated mice transplanted with Pdx1-transduced ASCs (Pdx1-ASCs) showed significantly decreased blood glucose levels and increased survival, when compared with control mice. While stable expression of Pdx1 in ASCs did not induce the pancreatic phenotype in vitro in our experiment, the transplanted stem cells became engrafted in the pancreas, wherein they expressed insulin and C-peptide, which is a marker of insulinproducing cells. These results suggest that Pdx1-ASCs are stably engrafted in the pancreas, acquire a functional beta-cell phenotype, and partially restore pancreatic function in vivo. The ease and safety associated with extirpating high numbers of cells from adipose tissues support the applicability of this system to developing a new cell therapy for IDDM.

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

“…Transplantation of PDX-1 transduced ADSCs into streptozotocine-induced diabetic mice reduced the blood glucose levels. In this study 25 % of the PDX-1-ADSCs transplanted into pancreas of the streptozotocine treated mice differentiated into insulin-producing cells (Kajiyama et al 2010). …”

“…Similar three-step differentiation protocol was able to differentiate the human adipose tissue-derived stem cells into IPCs (Chandra et al 2011). Kajiyama et al (2010) reported that PDX-1 transfected adipose tissue-derived stem cell can differentiate into insulin-producing cells. The human PDX-1 gene was integrated with retrovirus and transducted into ADSCs.…”

Applicability of Adipose-Derived Stem Cells in Type 1 Diabetes Mellitus

“…ADSCs were immunotyped and then further differentiated into IPCs for transplantation. An ongoing study (49) conducted an in vitro differentiation procedure to generate IPCs by transducing the transcription factor Pdx1, which is important for pancreatic b-cell differentiation. The researchers reported significantly decreased blood glucose levels and increased survival after tail vein injection of Pdx1-transduced ADSCs [immunotyping: paired box 6 (Pax6), Nk2 homeobox 2], wherein they expressed insulin and C-peptide.…”

Murine Insulinoma Cell-Conditioned Medium with ΒETA2/Neurod1 Transduction Efficiently Induces the Differentiation of Adipose-Derived Mesenchymal Stem Cells into β-Like Cells both In Vitro and In Vivo

“…Pdx1 cDNA was obtained as previously described [15]. The open reading frame of the human Pdx1 gene was integrated into the retrovirus vector pMSCV-puro.…”

“…PDX-1-deficient mice die rapidly after birth due to pancreatic insufficiency [14]. Previously, our research group demonstrated that Pdx1-transfected ADSCs can mature in vivo [15]. The combined expression of Pdx1 and MafA with either Ngn3 or NeuroD are required for both exocrine cell reprogramming and staging differentiation [16].…”