Lorenzo Piemonti
Lorenzo Piemonti
affiliation: San Raffaele Scientific Institute
research area(s): Experimental Medicine, Immunity And Infection
Course: Basic and Applied Immunology
University/Istitution: Università Vita-Salute San Raffaele
1994: MD, Universita degli Studi di Milano, Milan, Italy.
2000: Specialist in Endocrinolgy and metabolic disease, Universita degli Studi di Milano, Milan, Italy.
2004: Specialist in Micro and Experimental Surgery, Universita degli Studi di Milano, Milan, Italy.

Professional experiences
1990-1994 : Laboratory of Experimental Surgery, HSR, Milan (tutor Prof. Di Carlo Valerio)
1994-1996 : Fellow, Laboratory of Cellular Immunology, Inst. Pharmachological Research "MarioNegri", Milan (tutor Prof. Mantovani A).
1996-2001 : Laboratory of Experimental Surgery, HSR, Milan (tutor Prof Di Carlo Valerio).
2001-2002 : Laboratory of Diabetes Immunology, HSR, Milan (tutor Prof Ezio Bonifacio).
2002-2007 : Telethon-JDRF Center for Beta Cell Replacement, HSR, Milan (tutor Prof Ezio Bonifacio).
2008-today: Head of Beta Cell Biology Unit and Islet Core Facility, San Raffaele Diabetes Research Institute, (HSR-DRI), Milan, Italy.
2009-today: Co director of the Pancreatic Islet Transplantation Program, San Raffaele Diabetes Research Institute, (HSR-DRI), Milan, Italy.

Senior Investigator, Head of Experimental Endocrinology Unit and Islet Core Facility, Co director of the Pancreatic Islet Transplantation Program

Lorenzo Piemonti activity is mainly focused on pancreatology. In particular he has large experience about pancreatic cancer and type 1 diabetes. He has in the past studied the role of innate immunity in islet cell biology (especially in the human model of islet transplantation in type 1 diabetes recipient) and in pancreatic cancer biology (especially the role of chemokines and chemokine receptor system in inducing leukocytes infiltration). The other fields of activity were focused on dendritic cell biology and experimental oncology.

Specifically the ongoing project focuses at creating conditions that favour beta cell survival and expansion in transplanted and native environments. Specifically, he aim to:

1) Improve Islet Transplant. Novel approaches are needed to improve islet survival either immediately after transplantation, either in the long term.
As preclinical study we propose to:
a) Improve islet transplantation outcome by cotransplantation of islets and feeder cells using mesenchymal stem cells as feeder cells. The proposal is based on preliminary data showing that a large number of mesenchymal stem cells with proliferative capacity are retrieved in islet and non-islet fractions obtained from pancreas digestion. When cotransplated with pancreatic islets, pancreatic MSC favour survival and function of transplanted tissue.
b) Study bone marrow as site for islet transplantation. Survival of both syngeneic and allogeneic islet grafts in the liver is sub-optimal in the mouse model. We propose the bone marrow as an alternative site because of its accessibility, its environment rich in stem cells, and its potential for revascularization. Our data show that islets survive exceptionally well in mice, when transplanted into the bone marrow.
c) Develop novel islet survival strategies by modulating inflammation. Preventing early post-transplant islet loss remains a challenge. We propose the modulation of CCR2 and CXCR2 pathways as target to improve islet engraftment. The proposal is based on the finding that the CCR2 and CXCR2 pathways contribute to the survival and function of islets after transplantation in the liver both in man and in mouse using syngeneic transplant in CCL2 and CXCR2 KO models. We propose that specifically inhibiting pathways involving CCL2 or IL-8 will improve outcome and have identified therapeutic agents that can be tested in clinical trial.

2) to identify a renewable source of cells to be used to increase the transplantable beta cell mass in diabetic patients
The present part of our program inquires the possibility to isolate stem cells from adult/fetal tissue and to establish their differentiation potential toward insulin-secreting cells. We propose:
a) To study the potential of CD133+ intrapancreatic stem cells to be differentiated into beta cells. The proposal is based on the identification and isolation of a CD133+/EpCam+/Ca19.9+/CD73- tissue stem cells from digested human pancreas.
b) To study the potential of induced pluripotent stem cells (IPS) to be differentiated into beta cells. The proposal is based on the availability of human IPS in the department (Broccoli group) and of setted up protocols of differentiation of ES cells to beta cells.
c) To study the potential of amniocytes to be differentiated into beta cells. The proposal is based on the confirmation in our hand of the existence of a subpopulation of ckit positive human amniocytes. These cells were described to posses the ability to differentiate in all the embryonic lineages including endoderm.
d) To identify factor/s and pathways able to modulate the differentiation of pancreatic precursor by studing the expression of transcriptional factor involved in pancreas development in pancreatic cancer cell. The proposal is based on our evidence that pancreatic cancer cell express transcriptional factors involved in pancreas development.

3) to determine mechanisms of islet autoantigen immunization and destruction.
This is a collaborative project (DIAbetes type 1 Prediction, Early Pathogenesis and Prevention) that specifically addresses the call FP7 of European Community- Cooperation Work Programme: Health-2007-2.4.3-1 Early processes in the pathogenesis of type 1 diabetes and strategies for early prevention. The overall objective is to determine mechanisms of islet autoantigen immunization. The expected impact is new fundamental knowledge regarding i) how immunization against islet autoantigens can occur; ii) how signs of self-immunization can be exploited for prediction and monitoring of disease; and iii) how the immunization or its progression to islet beta cell destruction and T1D development can be prevented.

1: Sordi V, Piemonti L. Therapeutic plasticity of stem cells and allograft
tolerance. Cytotherapy. 2011 Jul;13(6):647-60.

2: Calori G, Lattuada G, Ragogna F, Garancini MP, Crosignani P, Villa M, Bosi E, Ruotolo G, Piemonti L, Perseghin G. Fatty liver index and mortality: The cremona study in the 15th year of follow-up. Hepatology. 2011 Jul;54(1):145-52. doi: 10.1002/hep.24356.

3: Zhou W, Capello M, Fredolini C, Piemonti L, Liotta LA, Novelli F, Petricoin
EF. Proteomic analysis of pancreatic ductal adenocarcinoma cells reveals
metabolic alterations. J Proteome Res. 2011 Apr 1;10(4):1944-52.

4: Piemonti L, Maffi P, Monti L, Lampasona V, Perseghin G, Magistretti P, Secchi A, Bonifacio E. Beta cell function during rapamycin monotherapy in long-term type 1 diabetes. Diabetologia. 2011 Feb;54(2):433-9.

5: Calori G, Lattuada G, Piemonti L, Garancini MP, Ragogna F, Villa M, Mannino S, Crosignani P, Bosi E, Luzi L, Ruotolo G, Perseghin G. Prevalence, metabolic features, and prognosis of metabolically healthy obese Italian individuals: the Cremona Study. Diabetes Care. 2011 Jan;34(1):210-5.

6: Smura T, Ylipaasto P, Klemola P, Kaijalainen S, Kyllönen L, Sordi V, Piemonti L, Roivainen M. Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: implications for pathogenesis. J Med Virol. 2010 Nov;82(11):1940-9.

7: Sordi V, Piemonti L. Mesenchymal stem cells as feeder cells for pancreatic
islet transplants. Rev Diabet Stud. 2010 Summer;7(2):132-43. Review.

8: Zhou W, Capello M, Fredolini C, Piemonti L, Liotta LA, Novelli F, Petricoin
EF. Mass spectrometry analysis of the post-translational modifications of
alpha-enolase from pancreatic ductal adenocarcinoma cells. J Proteome Res. 2010 Jun 4;9(6):2929-36.

9: 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.

10: Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of
perineural invasion, a forgotten pathway of dissemination and metastasis.
Cytokine Growth Factor Rev. 2010 Feb;21(1):77-82. Review.

11: Cainarca S, Fenu S, Ferri C, Nucci C, Arioli P, Menegon A, Piemonti L, Lohmer S, Wrabetz L, Corazza S. A photoprotein in mouse embryonic stem cells measures Ca2+ mobilization in cells and in animals. PLoS One. 2010 Jan 27;5(1):e8882.

12: Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta M,
Piemonti L, Capurso G, Di Florio A, delle Fave G, Pederzoli P, Croce CM, Scarpa A. Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol. 2010 Jan 10;28(2):245-55.

13: Piemonti L, Guidotti LG, Battaglia M. Modulation of early inflammatory
reactions to promote engraftment and function of transplanted pancreatic islets in autoimmune diabetes. Adv Exp Med Biol. 2010;654:725-47. Review.

14: Ciceri F, Piemonti L. Bone marrow and pancreatic islets: an old story with
new perspectives. Cell Transplant. 2010;19(12):1511-22. Review.

15: Melzi R, Mercalli A, Sordi V, Cantarelli E, Nano R, Maffi P, Sitia G,
Guidotti LG, Secchi A, Bonifacio E, Piemonti L. Role of CCL2/MCP-1 in islet
transplantation. Cell Transplant. 2010;19(8):1031-46.

16: 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. Erratum in: Stem Cells. 2010 Feb;28(2):386. Borg, Danielle [added].

17: 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

18: Piemonti L, Calori G, Lattuada G, Mercalli A, Ragogna F, Garancini MP,
Ruotolo G, Luzi L, Perseghin G. Association between plasma monocyte
chemoattractant protein-1 concentration and cardiovascular disease mortality in middle-aged diabetic and nondiabetic individuals. Diabetes Care. 2009

19: Malosio ML, Esposito A, Poletti A, Chiaretti S, Piemonti L, Melzi R, Nano R, Tedoldi F, Canu T, Santambrogio P, Brigatti C, De Cobelli F, Maffi P, Secchi A,Del Maschio A. Improving the procedure for detection of intrahepatic transplanted islets by magnetic resonance imaging. Am J Transplant. 2009 Oct;9(10):2372-82.

20: Melzi R, Maffi P, Nano R, Sordi V, Mercalli A, Scavini M, Secchi A, Bonifacio E, Piemonti L. Rapamycin does not adversely affect intrahepatic islet engraftment in mice and improves early islet engraftment in humans. Islets. 2009 Jul-Aug;1(1):42-9.
Project Title:
Human Induced pluripotent stem (hIPS) cells as a source of insulin producing cells
The overall objective of the proposal is to treat diabetes by using insulin producing cells obtained from human induced pluripotent stem cell (iPS). Very recent reports document that human iPS cells can give rise to insulin-producing cells (Tateishi et al., 2008 and Zhang et al., 2009). These findings raised the possibility that patient-specific stem cells derived from reprogramming could provide a treatment for diabetes.
Specifically we plan to:
1) demonstrate the possibility to efficiently generate iPS from diabetic patients
2) address the safety concern of iPS using three different strategies:
a) insertion of a suicide gene in iPS that would allow selective killing of any iPS cell-derived tumors
b) identification of cell membrane markers specific for posterior foregut, pancreatic endoderm and endocrine definitive endoderm commitment that would permit selection during differentiation excluding residual pluri/multi potent cells present in cell populations
c) test the feasibility of a biocompatible device that would allow the bidirectional exchange of soluble factors across the semipermeable membrane while keeping the transplanted cells physically isolated from direct contact with host tissue.
3) improve the efficacy and efficiency of iPS differentiation in insulin producing cell using three different strategies:
a) use of human pancreatic mesenchymal cell as feeder cell during the early stages of differentiation to mimic fetal mesenchyme-endoderm cross talk
b) use of decellularized human islets as Extracellular Matrix in culture during the late stages of differentiation to provide signals for maintaining cell vitality and endocrine commitment
c) identification and pharmacological modulation of new specific �master pathways� activated during the different stages of differentiation. For the identification of the �master pathways� we will compare the gene expression profile of Pdx1+ vs Pdx1-, Ngn3+ vs Ngn3-, insulin+ vs insulin- cells.

Project Title:
The goal of this study is to demonstrate, in a preclinical in vivo model, that co-transplantation and co-localization of mesenchymal stem cells and islets in bone marrow is effective at preventing the rejection and improving islet engraftment. The starting hypothesis is that BM represents an ideal
site to test co-injection of islets and MSC being the natural locus of development and function of stem cells and allowing the physical proximity of the two components
In particular we plan to:
- EVALUATE THE EFFICACY OF MSC CO-TX AND CO-LOCALIZATION TO PROMOTE THE ENGRAFTMENT OF ISLET TX AFTER INTRA BM INFUSION. We will test whether MSC co-transplanted and co-localized with islets are able to facilitate graft survival and function in a syngeneic marginal mass model of intra BM islet
- INVESTIGATE THE MECHANISMS USED BY MSC TO PROMOTE THE ENGRAFTMENT OF ISLETS. We will evaluate beta cell apoptosis, beta cell proliferation and transplanted islets neovascularization in the syngeneic models of islet transplant.
- STUDY MSC-MEDIATED MODULATION OF GENES AND PATHWAYS INVOLVED IN TISSUE REMODELLING. We will analyze the expression of selected genes related to inflammation and angiogenesis in BM in the syngeneic models of islet transplant.
- EVALUATE THE EFFICACY OF MSC CO-TRANSPLANTATION AND CO-LOCALIZATION TO IMPROVE ISLET SURVIVAL IN THE PRESENCE OF IMMUNE RESPONSE AFTER INTRA BM ISLET INFUSION We will test whether MSC cotransplanted and co-localized with islets in BM are able to improve islet survival in allogenic, autoimmune and allogenic+autoimmune models
- INVESTIGATE THE MECHANISMS USED BY MSC TO MODULATE THE IMMUNO RESPONSE. We will perform the characterization of leukocyte subpopulations in peripheral blood, spleen and BM in the allo/auto immune models and to test the ability of MSC to affect quantitatively and qualitatively the immune response against specific antigen expressed on beta cell of transplanted islets using RIPLCMV
transgenic mice.