title: Fibronectin and laminin promote differentiation of human mesenchymal stem cells into insulin producing cells through activating Akt and ERK.
abstract: BACKGROUND
  Islet 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).
  
  
  METHODS
  We used a four-stage differentiation protocol, containing neuronal differentiation and IPC-conversion stages, and combined with pellet suspension culture to induce IPC differentiation.
  
  
  RESULTS
  Here, 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Stem Cell Laboratory, Department of Medical Research and Education, Veterans General Hospital-Taipei, Taiwan.
authors.forename: Hsiao-Yun
authors.initials: HY
authors.lastname: Lin
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Tsai
authors.forename: Ling-Lan
authors.initials: LL
authors.lastname: Chen
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.forename: Yng-Jiin
authors.initials: YJ
authors.lastname: Wang
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
mesh_terms: D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D002867:Chromones; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology*; D005419:Flavonoids; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007797:Laminin / Q000378:metabolism / Q000494:pharmacology*; D016086:Lentivirus; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D009025:Morpholines; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002867:Chromones; D005353:Fibronectins; D005419:Flavonoids; D007797:Laminin; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one