title: Generation of insulin-producing cells from rat mesenchymal stem cells using an aminopyrrole derivative XW4.4.
abstract: Type 1 diabetes mellitus (T1DM), a multisystem disease with both biochemical and anatomical/structural consequences, is a major health concern worldwide. Pancreatic islet transplantation provides a promising treatment for T1DM. However, the limited availability of islet tissue or new sources of insulin producing cells (IPCs) that are responsive to glucose hinder this promising approach. Though slow, the development of pancreatic beta-cell lines from rodent or human origin has been steadily progressing. Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent, culture-expanded, non-hematopoietic cells that are currently being investigated as a novel cellular therapy. The in vitro differentiation potential of IPCs has raised hopes for a treatment of clinical diseases associated with autoimmunity. We screened for small molecules that induce pancreatic differentiation of IPCs. There are some compounds which showed positive effects on the DTZ staining. The aminopyrrole derivative compound XW4.4 which shows the best activity among them was found to induce pancreatic differentiation of rat MSCs (rMSCs). The in vitro studies indicated that treatment of rMSCs with compound XW4.4 resulted in differentiated cells with characteristics of IPCs including islet-like clusters, spherical, grape-like morphology, insulin secretion, positive for dithizone, glucose stimulation and expression of pancreatic endocrine cell marker genes. The data has also suggested that hepatocyte nuclear factor 3β (HNF 3β) may be involved in pancreatic differentiation of rMSCs when treated with XW4.4. Results indicate that XW4.4 induced rMSCs support the efforts to derive functional IPCs and serve as a means to alleviate limitations surrounding islet cell transplantation in the treatment of T1DM.
authors.affiliation: Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, No 866, Yuhangtang Road, Hangzhou, Zhejiang 310058, China; Morphology Laboratory, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Ouyang
authors.affiliation: Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, No 866, Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, No 866, Yuhangtang Road, Hangzhou, Zhejiang 310058, China.
authors.forename: Wanwan
authors.initials: W
authors.lastname: Yu
authors.affiliation: Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, No 866, Yuhangtang Road, Hangzhou, Zhejiang 310058, China; The First People's Hospital of Jiande, Hangzhou, Zhejiang Province 311600, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Torrey Pines Institute for Molecular Studies, Port St Lucie, FL 34987, USA.
authors.forename: Ramanjaneya V R
authors.initials: RV
authors.lastname: Mula
authors.affiliation: Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, No 866, Yuhangtang Road, Hangzhou, Zhejiang 310058, China. Electronic address: zouhb@zju.edu.cn.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Zou
authors.affiliation: Institute of Materia Medica, College of Pharmaceutical Sciences, Zhejiang University, No 866, Yuhangtang Road, Hangzhou, Zhejiang 310058, China. Electronic address: yyu@zju.edu.cn.
authors.forename: Yongping
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000818:Animals; D002096:C-Peptide / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology*; D005260:Female; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D002096:C-Peptide; D007328:Insulin; D054852:Small Molecule Libraries; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: DMEM; Dulbecco’s minimum essential medium; EDTA; EGF; FBS; HNF 3β; IPCs; Insulin-producing cells; MSCs; Mesenchymal stem cells; NEAA; PDX-1; Pancreatic differentiation; RT-PCR; Small molecules; T1DM; bFGF; basic fibroblast growth factor; epidermal growth factor; ethylenedia-minetetraacetic acid; fetal bovine serum; hepatocyte nuclear factor 3β; insulin-producing cells; mesenchymal stem cells; non-essential amino acid; pancreatic duodenal homeobox-1; reverse-transcription polymerase chain reactions; type 1 diabetes mellitus