Human umbilical cord Wharton jelly cells promote extra-pancreatic insulin formation and repair of renal damage in STZ-induced diabetic mice

Cell Communication and Signaling, Oct 2017

We evaluated the therapeutic effect and fate of high doses of human umbilical cord Wharton jelly cells (hUCWJCs) after IP administration to streptozotocin (STZ)-induced diabetic mice. Type 1 diabetes (T1D) was induced in Kunming mice via IP injection of STZ. hUCWJCs were labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI). Diabetic animals with sustained hyperglycemia for at least 2 weeks were administered 1 × 107 Dil-hUCWJCs via intraperitoneal injection. Insulin, glucagon and PDX-1 were detected by immunofluorescence with confocal microscopy. Serum mouse and human C-peptide was assayed in blood collected via intracardiac puncture. Specific β-cell differentiation markers and human DNA were assessed using qPCR performed with 200 ng of target DNA. hUCWJCs migrated to the STZ-damaged organs and contributed to lower blood glucose levels in 30% of the treated mice. Confocal microscopy revealed the presence of resident insulin-positive cells in the liver and kidneys. hUCWJC-treated mice with restored hyperglycemia also showed increased serum mouse C-peptide levels. The qPCR results, particularly in the liver, revealed that after transplantation hUCWJCs upregulated genes of endocrine precursors but failed to express endocrine stage markers. Mice with restored hyperglycemia had reduced urinary volume and lacked glomerular hypertrophy, exhibiting a morphology resembling that of normal glomeruli. Moreover, we also verified that one of the possible mechanisms by which hUCWJCs exert immunosuppressive effects is through down-regulation of the cell surface receptor HLA-1. We confirmed the potential of IP administration of hUCWJCs and the capability of these cells to migrate to damaged tissues and promote insulin secretion from non-pancreatic local cells and to improve renal damage. These findings confer unique therapeutic properties to hUCWJCs, suggesting a promising future in the treatment of diabetes mellitus.

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Human umbilical cord Wharton jelly cells promote extra-pancreatic insulin formation and repair of renal damage in STZ-induced diabetic mice

Maldonado et al. Cell Communication and Signaling Human umbilical cord Wharton jelly cells promote extra-pancreatic insulin formation and repair of renal damage in STZ-induced diabetic mice Martin Maldonado 0 1 2 3 4 7 Tianhua Huang 2 7 Lujun Yang 0 3 8 Lan Xu 2 Lian Ma 0 1 3 4 5 6 0 Translational Medical Center, Second Affiliated Hospital of Shantou University Medical College , 22 Xinling road, Shantou, Guangdong 515041 , People's Republic of China 1 Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College , Shantou, Guangdong 515041 , People's Republic of China 2 Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Research Center for Reproductive Medicine, Shantou University Medical College , Shantou 515041 , People's Republic of China 3 Translational Medical Center, Second Affiliated Hospital of Shantou University Medical College , 22 Xinling road, Shantou, Guangdong 515041 , People's Republic of China 4 Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College , Shantou, Guangdong 515041 , People's Republic of China 5 Department of Pediatrics, Maternal and Child Health Care Hospital of Pingshan District , 518122 Shenzhen, Guangdong , People's Republic of China 6 Department of Pediatrics, Maternal and Child Health Care Hospital of Shenzhen University , 518052 Shenzhen, Guangdong , People's Republic of China 7 Reproductive Medicine & Genetics, Chengdu Jinjiang Hospital for Maternal & Child Health Care , Chengdu 610066 , China 8 Department of Burns and Plastic Surgery, Second Affiliated Hospital of Shantou University Medical College , Shantou, Guangdong 515041 , People's Republic of China Background: We evaluated the therapeutic effect and fate of high doses of human umbilical cord Wharton jelly cells (hUCWJCs) after IP administration to streptozotocin (STZ)-induced diabetic mice. Methods: Type 1 diabetes (T1D) was induced in Kunming mice via IP injection of STZ. hUCWJCs were labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI). Diabetic animals with sustained hyperglycemia for at least 2 weeks were administered 1 × 107 Dil-hUCWJCs via intraperitoneal injection. Insulin, glucagon and PDX-1 were detected by immunofluorescence with confocal microscopy. Serum mouse and human C-peptide was assayed in blood collected via intracardiac puncture. Specific β-cell differentiation markers and human DNA were assessed using qPCR performed with 200 ng of target DNA. Results: hUCWJCs migrated to the STZ-damaged organs and contributed to lower blood glucose levels in 30% of the treated mice. Confocal microscopy revealed the presence of resident insulin-positive cells in the liver and kidneys. hUCWJC-treated mice with restored hyperglycemia also showed increased serum mouse C-peptide levels. The qPCR results, particularly in the liver, revealed that after transplantation hUCWJCs upregulated genes of endocrine precursors but failed to express endocrine stage markers. Mice with restored hyperglycemia had reduced urinary volume and lacked glomerular hypertrophy, exhibiting a morphology resembling that of normal glomeruli. Moreover, we also verified that one of the possible mechanisms by which hUCWJCs exert immunosuppressive effects is through down-regulation of the cell surface receptor HLA-1. Conclusions: We confirmed the potential of IP administration of hUCWJCs and the capability of these cells to migrate to damaged tissues and promote insulin secretion from non-pancreatic local cells and to improve renal damage. These findings confer unique therapeutic properties to hUCWJCs, suggesting a promising future in the treatment of diabetes mellitus. Human umbilical cord Wharton jelly cells; Diabetes type-1; Streptozotocin; Intraperitoneal administration; Insulin Background Type 1 diabetes (T1D) is an autoimmune disease characterized by T-cell–mediated destruction of insulinproducing β–cells [ 29 ]. The reversal of T1D involves whole pancreas or islet cell transplantation in association with nonspecific immunosuppressive therapy [ 38 ]. Immunosuppressive therapy not only results in compromised immune function but has the potential for additional complications with long-term use. Due to the mentioned limitations, the use of embryonic stem cells (ESCs), cord blood–derived SCs, adult SCs, bone marrow, genetically engineered cells and mesenchymal stem cells (MSCs) among others are under exhaustive testing with the aim of reversing hyperglycemia [ 1, 3, 19, 22, 46, 56–58 ]. Among the different types of MSCs, Human Umbilical Cord Wharton Jelly Cells (hUCWJCs) appear to offer the best clinical advantage due to their unique beneficial characteristics [ 5 ]. hUCWJCs are located in a specific mucous proteoglycanrich matrix known as Wharton’s jelly, which is present in the umbilical cord and derived from the extra-embryonic mesoderm. hUCWJCs share an early developmental origin, multilineage (...truncated)


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Martin Maldonado, Tianhua Huang, Lujun Yang, Lan Xu, Lian Ma. Human umbilical cord Wharton jelly cells promote extra-pancreatic insulin formation and repair of renal damage in STZ-induced diabetic mice, Cell Communication and Signaling, 2017, pp. 43,