Human Insulin Secreted from Insulinogenic Xenograft Restores Normoglycemia in Type 1 Diabetic Mice without Immunosuppression

Abstract

In the present study, we examined the therapeutic potential of human amnion-derived insulin-secreting cells for type 1 diabetes. Human amniotic mesenchymal stem cells (hAMs) were isolated from amnion and cultivated to differentiate into insulin-secreting cells in vitro. After culture in vitro, the differentiated cells (hAM-ISCs) were intensively stained with dithizone and secreted insulin and c-peptide in a high-glucose-dependent manner. They expressed mRNAs of pancreatic cell-related genes, including INS, PDX1, Nkx6-1, NEUROG3, ISL1, NEUROD1, GLUT1, GLUT2, PC1/3, PC2, GCK, PPY, SST, and GC, and were positive for human insulin and c-peptide. Transplantation of hAM-ISCs into the kidneys of mice with streptozotocin-induced diabetes restored body weight and normalized the blood glucose levels, which lasted for 210 days. Only human insulin and c-peptide were detected in the blood of normalized mice after 2 months of transplantation, but little mouse insulin and c-peptide. Removal of graft-bearing kidneys from these mice resulted in causing hyperglycemia again. Human cell-specific gene, hAlu, and human pancreatic cell-specific genes, insulin, PDX1, GLUT1, GLP1R, Nkx6-1, NEUROD1, and NEUROG3, were detected in the graft-bearing kidneys. Colocalization of human insulin and human nuclei antigen was also observed. These results demonstrate that hAMs could differentiate into functional insulin-secreting cells in vitro, and human insulin secreted from hAM-ISCs following transplantation into type 1 diabetic mice could normalize hyperglycemia, overcoming immune rejection for a long period.

Concise Review: Fetal Membranes in Regenerative Medicine: New Tricks from an Old Dog?

“…However, protein expression of human insulin, glucagon, and somatostatin was only detected in differentiated cells. The differentiated ILC also showed abundance of pancreatic transcription factors ngn3 and isl1, and were able to secrete insulin in response to glucose . Transplantation of undifferentiated hCMSC or differentiated ILC in STZ‐induced diabetic mice restored normoglycemia .…”

“…Long‐term cultures of hCMSC have been successfully maintained while retaining their ability to differentiate into adipogenic, oesteogenic, chondrogenic, and neuronal lineages . hCMSC can also form islet‐like cell clusters (ILC) on stepwise exposure to serum‐free differentiation media.…”

“…hCMSC can also form islet‐like cell clusters (ILC) on stepwise exposure to serum‐free differentiation media. Gene transcriptional studies indicate that both undifferentiated hCMSC and ILC expressed insulin, glucagon, and somatostatin . However, protein expression of human insulin, glucagon, and somatostatin was only detected in differentiated cells.…”

“…In a rat model of PD with 6-hydroxydopamine lesions, a higher survival rate of dopaminergic neurons was reported, along with an increase in dopaminergic neurons in the substantia nigra and restrained stem cells growth [75]. Transplantation of hAEC into a rat model of spinal cord injury significantly reduced mechanical allodynia [76], suggesting that hAEC transplantation hCMSC [66] Myocardial infarction hAMSC [63][64][65] hCMSC [67] Stroke hAEC [68,69] Neurological Traumatic brain injury hAMSC [71] Spinal cord injury hAMSC [72] hAEC [76] Optic nerve crush injury hCMSC [73] Encephalomyelitis hAEC [74] Parkinson's Disease hAEC [75] Diabetes hAEC [77] hAMSC [78,79] hCMSC [80] Gastrointestinal Proctitis hAMSC [81] Colitis hAMSC [82] liver fibrosis hCMSC [83] hAEC [84,85] Respiratory Pulmonary fibrosis hAEC [49,50,108] hAMSC, hCMSC [87] Chronic obstructive pulmonary disease hAEC [91] Asthma hAEC [92] Bronchopulmonary dysplasia hAEC [93,94] hCMSC [95] Cystic fibrosis hAMSC [96] hAEC [97] Abbreviations: hAEC, human amnion epithelial cells; hAMSC, human amnion mesenchymal stem cells; hCMSCs, human chorionic mesenchymal stem cells. [76].…”

Mesenchymal Stem or Stromal Cells from Amnion and Umbilical Cord Tissue and Their Potential for Clinical Applications

“…It has been reported that hAMSC and UC-MSC possess an immunoprivileged status as well, which is in part due to the expression of low to moderate levels of surface MHC-I, and the presence of low or even absent levels of MHC II and costimulatory molecules (e.g., CD40, CD80, CD86) [6,8,11,19,55,65,129,130,131]. …”