Vector-free in vivo trans-determination of adult hepatic stem cells to insulin-producing cells
- 30 Downloads
A reduction in the number of functional β-cells is the central pathological event in diabetes. Liver and ventral pancreas differentiates simultaneously in the same general domain of cells within embryonic endoderm. In addition, the precursor cell population being bi-potential may be targeted for either pancreas or liver development. Hepatic stem cells were redirected in vivo to functional insulin producing cells in a acetylaminofluorene–partial hepatectomy (AAF/PH) adult male rat model with/without GLP-1 treatment. In routine H&E histology and immunohistochemistry, stem cells resembled β cells in GLP-1 injected rats. Immunoblots revealed involvement of adenylate cyclase, TLR4 and PDX1 in insulin synthesis. Expression of genes (GLP-1R, MAFA, PDX1, INS1 and INS2) augmented in the GLP-1 treated regenerated liver. Results strongly indicated the key role of GLP-1 in the induction of insulin secretion in trans-determined reprogrammed cell in vivo. The present method being vector free poses no risk of vector spillover in the host and holds promise.
KeywordsStem cell β-Like cell GLP-1 Vector free trans-determination
Authors gratefully acknowledge National Academy of Sciences, India for providing research grant in the NASI Honorary Scientist Scheme.
All authors contributed equally in experimental design and manuscript preparation. SS contributed in hepatectomy, Western blotting and gene expression; CM contributed in histology and immunohistochemistry; SM contributed in FACS analysis.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Deutsch G, Jung J, Zheng M, Lóra J, Zaret KS (2001) A bipotential precursor for pancreas and liver within the embryonic endoderm. Development 128:871–881Google Scholar
- 5.Zhu S, Russ HA, Wang X, Zhang M, Ma T, Xu T, Ding S (2016) Human pancreatic beta-like cells converted from fibroblasts. Nat Commun 7:1–13Google Scholar
- 8.Liu J, Liu Y, Wang H, Hao H, Han Q, Shen J, Shi J, Li C, Han W (2013) Direct differentiation of hepatic stem-like WB cells into insulin-producing cells using small molecules. Sci Rep 3:1–8Google Scholar
- 17.Atala A, Lanza RP (2001) Preface. In: Atala A, Lanza RP (eds) Methods of tissue engineering. Academic Press, San Diego, pp 83–96Google Scholar
- 24.Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Measurement of protein with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
- 27.Kanherkar RR, Bhatia-Dey N, Makarev E, Csoka AB (2014) Cellular reprogramming for understanding and treating human disease. Front Cell Dev Biol 2:1–21Google Scholar
- 28.Balogh P, Engelmann P (2011) Transdifferentiation and regenerative medicine. University of Pécs, Pécs, pp 1–88Google Scholar
- 38.Portha B, Tourrel-Cuzin C, Movassat J (2011) Activation of the GLP-1 receptor signalling pathway: a relevant strategy to repair a deficient Beta-cell mass. Exp Diabetes Res 376509:11Google Scholar