Diabetes research institute
Beta Cell Differentiation
Beta cells in the pancreas secrete insulin and control blood glucose level. Beta cell mass deficiency characterizes both type 1 diabetes, in which beta cells are destroyed by an autoimmune attack, and type 2 diabetes, in which beta cells are dysfunctional and undergo apoptosis. Clinical and experimental islet transplantation demonstrate that it is possible to replace beta cell mass, restoring normoglycemia. Unfortunately, this approach is strongly limited by the scarcity of donors and the need for lifelong immunosuppression of transplant recipients. A new infinite source of insulin producing beta cells would then represent a major advance in the field.
Research activity
We generate new functional beta cells from pluripotent stem cells. Differentiation of ESC/iPSC into beta cells in vitro follows pancreatic developmental stages, from pluripotency to definitive endoderm, then to posterior foregut cells, pancreatic endoderm, endocrine progenitors and finally to insulin-producing mature beta cells. We set up protocols, optimized for several pluripotent cell lines, established all the relevant read-outs, compared the final product with human islets from organ donors, analysed the transcriptome of the cell during differentiation at single cell level. Moreover, in the unit we transplant stem cell-derived beta in cells in diabetic mouse model, follow the function in vivo and investigate strategies to improve the engraftment and survival, like co- transplantation of feeder cells, modulation of graft microenvironment, or to control the immune reaction to the graft.
Generation of beta cells from stem cells is also a tool for the study of beta cell physiology and pathology, for instance it provides tools for disease modelling of genetic disease with mutations affecting the beta cells, like monogenic diabetes of the adult (MODY) or Wolfram syndrome.
Maffi P, Lundgren T, Tufveson G, Rafael E, Shaw JAM, Liew A, Saudek F, Witkowski P, Golab K, Bertuzzi F, Gustafsson B, Daffonchio L, Ruffini PA, Piemonti L; REP0211 Study Group. Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes. Diabetes Care. 2020 Apr;43(4):710-718. doi: 10.2337/dc19-1480.
Pellegrini S, Cantarelli E, Citro A, Incerti E, Piemonti L, Sordi V. Selective local irradiation improves islet engraftment and survival in intra-bone marrow islet transplantation. Cytotherapy. 2019 Oct;21(10):1025-1032. doi: 10.1016/j.jcyt.2019.07.005.
Nava S, Sordi V, Pascucci L, Tremolada C, Ciusani E, Zeira O, Cadei M, Soldati G, Pessina A, Parati E, Slevin M, Alessandri G. Long-Lasting Anti-Inflammatory Activity of Human Microfragmented Adipose Tissue. Stem Cells Int. 2019 Feb 19;2019:5901479. doi: 10.1155/2019/5901479.
Dugnani E, Sordi V, Pellegrini S, Chimienti R, Marzinotto I, Pasquale V, Liberati D, Balzano G, Doglioni C, Reni M, Gandolfi A, Falconi M, Lampasona V, Piemonti L. Gene expression analysis of embryonic pancreas development master regulators and terminal cell fate markers in resected pancreatic cancer: A correlation with clinical outcome. Pancreatology. 2018 Dec;18(8):945-953. doi: 10.1016/j.pan.2018.09.006.
Pellegrini S, Manenti F, Chimienti R, Nano R, Ottoboni L, Ruffini F, Martino G, Ravassard P, Piemonti L, Sordi V. Differentiation of Sendai Virus-Reprogrammed iPSC into β Cells, Compared with Human Pancreatic Islets and Immortalized β Cell Line. Cell Transplant. 2018 Oct;27(10):1548-1560. doi: 10.1177/0963689718798564.
Maffi P, Nano R, Monti P, Melzi R, Sordi V, Mercalli A, Pellegrini S, Ponzoni M, Peccatori J, Messina C, Nocco A, Cardillo M, Scavini M, Magistretti P, Doglioni C, Ciceri F, Bloem SJ, Roep BO, Secchi A, Piemonti L. Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial. Transplantation. 2019 Apr;103(4):839-851. doi: 10.1097/TP.0000000000002416.
Pellegrini S, Piemonti L, Sordi V. Pluripotent stem cell replacement approaches to treat type 1 diabetes. Curr Opin Pharmacol. 2018 Dec;43:20-26. doi: 10.1016/j.coph.2018.07.007.
Sebastiani G, Valentini M, Grieco GE, Ventriglia G, Nigi L, Mancarella F, Pellegrini S, Martino G, Sordi V, Piemonti L, Dotta F. MicroRNA expression profiles of human iPSCs differentiation into insulin-producing cells. Acta Diabetol. 2017 Mar;54(3):265-281. doi: 10.1007/s00592-016-0955-9.
Sordi V, Ferri A, Ceserani V, Ciusani E, Dugnani E, Pellegrini S, Nano R, Pecciarini L, Pessina A, Pascucci L, Piemonti L, Alessandri G. Establishment, characterization and long-term culture of human endocrine pancreas-derived microvascular endothelial cells. Cytotherapy. 2017 Jan;19(1):141-152. doi: 10.1016/j.jcyt.2016.10.005.
Peloso A, Urbani L, Cravedi P, Katari R, Maghsoudlou P, Fallas ME, Sordi V, Citro A, Purroy C, Niu G, McQuilling JP, Sittadjody S, Farney AC, Iskandar SS, Zambon JP, Rogers J, Stratta RJ, Opara EC, Piemonti L, Furdui CM, Soker S, De Coppi P, Orlando G. The Human Pancreas as a Source of Protolerogenic Extracellular Matrix Scaffold for a New- generation Bioartificial Endocrine Pancreas. Ann Surg. 2016 Jul;264(1):169-79. doi: 10.1097/SLA.0000000000001364.
Pellegrini S, Ungaro F, Mercalli A, Melzi R, Sebastiani G, Dotta F, Broccoli V, Piemonti L, Sordi V. Human induced pluripotent stem cells differentiate into insulin-producing cells able to engraft in vivo. Acta Diabetol. 2015 Dec;52(6):1025-35. doi: 10.1007/s00592-015-0726-z.
Melzi R, Antonioli B, Mercalli A, Battaglia M, Valle A, Pluchino S, Galli R, Sordi V, Bosi E, Martino G, Bonifacio E, Doglioni C, Piemonti L. Co-graft of allogeneic immune regulatory neural stem cells (NPC) and pancreatic islets mediates tolerance, while inducing NPC-derived tumors in mice. PLoS One. 2010 Apr 27;5(4):e10357. doi: 10.1371/journal.pone.0010357.
Sordi V, Melzi R, Mercalli A, Formicola R, Doglioni C, Tiboni F, Ferrari G, Nano R, Chwalek K, Lammert E, Bonifacio E, Borg D, Piemonti L. Mesenchymal cells appearing in pancreatic tissue culture are bone marrow-derived stem cells with the capacity to improve transplanted islet function. Stem Cells. 2010 Jan;28(1):140-51. doi: 10.1002/stem.259.
Cantarelli E, Melzi R, Mercalli A, Sordi V, Ferrari G, Lederer CW, Mrak E, Rubinacci A, Ponzoni M, Sitia G, Guidotti LG, Bonifacio E, Piemonti L. Bone marrow as an alternative site for islet transplantation. Blood. 2009 Nov 12;114(20):4566-74. doi: 10.1182/blood-2009-03-209973.
Sordi V, Malosio ML, Marchesi F, Mercalli A, Melzi R, Giordano T, Belmonte N, Ferrari G, Leone BE, Bertuzzi F, Zerbini G, Allavena P, Bonifacio E, Piemonti L. Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood. 2005 Jul 15;106(2):419-27. doi: 10.1182/blood-2004-09-3507.
