Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation.
BACKGROUND
Mesenchymal stem cells (MSCs), also known as multipotent progenitor cells, release several factors that support cell survival and enhance wound healing. We hypothesized that MSC-secreted molecules would induce a trophic effect in pancreatic islet culture conditions.


METHODS
Pancreatic islets were co-cultured with MSCs, and ADP/ATP ratios, glucose stimulated insulin secretion (GSIS), and DNA fragmentation were evaluated to measure islet quality and viability in vitro. The induction of signal molecules related to the control of survival, function, and angiogenesis was also analyzed. Cell quality assays, DNA fragmentation assays, and islet transplantation into streptozotocin-induced diabetic mice were performed using MSC-conditioned medium (CM)-cultured islets. Furthermore, we identified soluble molecules within MSC-CM.


RESULTS
Islets co-cultured with MSCs demonstrated lower ADP/ATP ratios, and higher GSIS indexes and viability. Furthermore, co-cultured islets revealed higher levels of anti-apoptotic signal molecules (X-linked inhibitor of apoptosis protein, Bcl-xL, Bcl-2, and heat shock protein-32) and demonstrated increased vascular endothelial growth factor receptor 2 and Tie-2 mRNA expression and increased levels of phosphorylated Tie-2 and focal adhesion kinase protein. Islets cultured in MSC-CM demonstrated lower ADP/ATP ratios, less apoptosis, and a higher GSIS indexes. Diabetic mice that received islet transplants (200 islet equivalent) cultured in MSC-CM for 48 hr demonstrated significantly lower blood glucose levels and enhanced blood vessel formation. In addition, interleukin-6, interleukin-8, vascular endothelial growth factor-A, hepatocyte growth factor, and transforming growth factor-beta were detected at significant levels in MSC-CM.


CONCLUSIONS
These results suggest that the trophic factors secreted by human MSCs enhance islet survival and function after transplantation.
Park
Ki-Soo
KS
Department of Molecular Medicine, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Kim
Young-Seok
YS
Kim
Jae-Hyeon
JH
Choi
Bongkum
B
Kim
Sa-Hyun
SH
Tan
Alice Hyun-Kyung
AH
Lee
Myung-Shik
MS
Lee
Moon-Kyu
MK
Kwon
Choon-Hyuck
CH
Joh
Jae-Won
JW
Kim
Sung-Joo
SJ
Kim
Kwang-Won
KW
D000230:Adenocarcinoma; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002470:Cell Survival; D018920:Coculture Techniques; D003110:Colonic Neoplasms; D005312:Fetal Blood / Q000166:cytology; D005951:Glucose Tolerance Test; D006801:Humans; D007515:Islets of Langerhans / Q000098:blood supply / Q000166:cytology; D016381:Islets of Langerhans Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D014945:Wound Healing
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate