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Brandt EGS, Müller CF, Thomsen H, Rodell AB, Ibragimov B, Andersen MB. Imaging the pancreas with photon-counting CT - A review of normal pancreatic anatomy. Eur J Radiol 2024; 181:111736. [PMID: 39307069 DOI: 10.1016/j.ejrad.2024.111736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Revised: 09/05/2024] [Accepted: 09/11/2024] [Indexed: 12/19/2024]
Abstract
PURPOSE Compared to conventional energy integrating detector CT, Photon-Counting CT (PCCT) has the advantage of increased spatial resolution. The pancreas is a highly complex organ anatomically. The increased spatial resolution of PCCT challenges radiologists' knowledge of pancreatic anatomy. The purpose of this review was to review detailed macroscopic and microscopic anatomy of the pancreas in the context of current and future PCCT. METHOD This review is based on a literature review of all parts of pancreatic anatomy and a retrospective imaging review of PCCT scans from 20 consecutively included patients without pancreatic pathology (mean age 61.8 years, 11 female), scanned in the workup of pancreatic cancer with a contrast enhanced multiphase protocol. Two radiologists assessed the visibility of the main and accessory pancreatic ducts, side ducts, ampulla, major papilla, minor papilla, pancreatic arteries and veins, regional lymph nodes, coeliac ganglia, and coeliac plexus. RESULTS The macroscopic anatomy of the pancreas was consistently visualized with PCCT. Visualization of detailed anatomy of the ductal system (including side ducts), papillae, arteries, vein, lymph nodes, and innervation was possible in 90% or more of patients with moderate to good interreader agreement. CONCLUSION PCCT scans of the pancreas visualizes previously unseen or inconsistently seen small anatomical structures consistently. Increased knowledge of pancreatic anatomy could have importance in imaging of pancreatic cancer and other pancreatic diseases.
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Affiliation(s)
- Erik G S Brandt
- Department of Radiology, Herlev Hospital, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Denmark; Siemens Healthcare A/S, Borupvang 9, Ballerup, Denmark.
| | - Christoph F Müller
- Department of Radiology, Herlev Hospital, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Denmark
| | - Henrik Thomsen
- Department of Radiology, Herlev Hospital, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Denmark
| | | | - Bulat Ibragimov
- Department of Computer Sciences, University of Copenhagen, Denmark
| | - Michael B Andersen
- Department of Radiology, Herlev Hospital, Borgmester Ib Juuls Vej 1, DK-2730 Herlev, Denmark
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Zhang W, Cui Y, Lu M, Xu M, Li Y, Song H, Luo Y, Song J, Yang Y, Wang X, Liao L, Wang Y, Reid L, He Z. Hormonally and chemically defined expansion conditions for organoids of biliary tree Stem Cells. Bioact Mater 2024; 41:672-695. [PMID: 39309110 PMCID: PMC11415613 DOI: 10.1016/j.bioactmat.2024.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 07/25/2024] [Accepted: 08/13/2024] [Indexed: 09/25/2024] Open
Abstract
Wholly defined ex vivo expansion conditions for biliary tree stem cell (BTSC) organoids were established, consisting of a defined proliferative medium (DPM) used in combination with soft hyaluronan hydrogels. The DPM consisted of commercially available Kubota's Medium (KM), to which a set of small molecules, particular paracrine signals, and heparan sulfate (HS) were added. The small molecules used were DNA methyltransferase inhibitor (RG108), TGF- β Type I receptor inhibitor (A83-01), adenylate cyclase activator (Forskolin), and L-type Ca2+ channel agonist (Bay K8644). A key paracrine signal proved to be R-spondin 1 (RSPO1), a secreted protein that activates Wnts. Soluble hyaluronans, 0.05 % sodium hyaluronate, were used with DPM to expand monolayer cultures. Expansion of organoids was achieved by using DPM in combination with embedding organoids in Matrigel that was replaced with a defined thiol-hyaluronan triggered with PEGDA to form a hydrogel with a rheology [G*] of less than 100 Pa. The combination is called the BTSC-Expansion-Glycogel-System (BEX-gel system) for expanding BTSCs as a monolayer or as organoids. The BTSC organoids were expanded more than 3000-fold ex vivo in the BEX-gel system within 70 days while maintaining phenotypic traits indicative of stem/progenitors. Stem-cell-patch grafting of expanded BTSC organoids was performed on the livers of Fah-/- mice with tyrosinemia and resulted in the rescue of the mice and restoration of their normal liver functions. The BEX-gel system for BTSC organoid expansion provides a strategy to generate sufficient numbers of organoids for the therapeutic treatments of liver diseases.
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Affiliation(s)
- Wencheng Zhang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yangyang Cui
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Postgraduate Training Base of Shanghai East Hospital, Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Mengqi Lu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Postgraduate Training Base of Shanghai East Hospital, Jinzhou Medical University, Jinzhou, Liaoning, 121001, China
| | - Mingyang Xu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yuting Li
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Haimeng Song
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yi Luo
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Jinjia Song
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yong Yang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China
| | - Xicheng Wang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Lijun Liao
- Department of Anesthesiology and Pain Management, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, China
| | - Yunfang Wang
- Hepatobiliary and Pancreatic Center, Medical Research Center, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China
| | - Lola Reid
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, United States
| | - Zhiying He
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
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Bourgeois S, Coenen S, Degroote L, Willems L, Van Mulders A, Pierreux J, Heremans Y, De Leu N, Staels W. Harnessing beta cell regeneration biology for diabetes therapy. Trends Endocrinol Metab 2024; 35:951-966. [PMID: 38644094 DOI: 10.1016/j.tem.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/21/2024] [Accepted: 03/21/2024] [Indexed: 04/23/2024]
Abstract
The pandemic scale of diabetes mellitus is alarming, its complications remain devastating, and current treatments still pose a major burden on those affected and on the healthcare system as a whole. As the disease emanates from the destruction or dysfunction of insulin-producing pancreatic β-cells, a real cure requires their restoration and protection. An attractive strategy is to regenerate β-cells directly within the pancreas; however, while several approaches for β-cell regeneration have been proposed in the past, clinical translation has proven challenging. This review scrutinizes recent findings in β-cell regeneration and discusses their potential clinical implementation. Hereby, we aim to delineate a path for innovative, targeted therapies to help shift from 'caring for' to 'curing' diabetes.
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Affiliation(s)
- Stephanie Bourgeois
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Sophie Coenen
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Laure Degroote
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Lien Willems
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Annelore Van Mulders
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Julie Pierreux
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Yves Heremans
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium
| | - Nico De Leu
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; Endocrinology, Universiteit Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium; Endocrinology, ASZ Aalst, 9300 Aalst, Belgium.
| | - Willem Staels
- Genetics, Reproduction, and Development (GRAD), Beta Cell Neogenesis (BENE) Research Unit, Vrije Universiteit Brussel (VUB), 1090 Brussels, Belgium; Pediatric Endocrinology, Department of Pediatrics, KidZ Health Castle, Universiteit Ziekenhuis Brussel (UZ Brussel), 1090 Brussels, Belgium.
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Maluchenko A, Maksimov D, Antysheva Z, Krupinova J, Avsievich E, Glazova O, Bodunova N, Karnaukhov N, Feidorov I, Salimgereeva D, Voloshin M, Volchkov P. Molecular Basis of Pancreatic Neuroendocrine Tumors. Int J Mol Sci 2024; 25:11017. [PMID: 39456803 PMCID: PMC11507569 DOI: 10.3390/ijms252011017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/20/2024] [Accepted: 09/21/2024] [Indexed: 10/28/2024] Open
Abstract
Pancreatic neuroendocrine tumors (NETs) are rare well-differentiated neoplasms with limited therapeutic options and unknown cells of origin. The current classification of pancreatic neuroendocrine tumors is based on proliferative grading, and guides therapeutic strategies, however, tumors within grades exhibit profound heterogeneity in clinical manifestation and outcome. Manifold studies have highlighted intra-patient differences in tumors at the genetic and transcriptomic levels. Molecular classification might become an alternative or complementary basis for treatment decisions and reflect tumor biology, actionable cellular processes. Here, we provide a comprehensive review of genomic, transcriptomic, proteomic and epigenomic studies of pancreatic NETs to elucidate patterns shared between proposed subtypes that could form a foundation for new classification. We denote four NET subtypes with distinct molecular features, which were consistently reproduced using various omics technologies.
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Affiliation(s)
- Alesia Maluchenko
- Moscow Center for Advanced Studies, Kulakova Str. 20, Moscow 123592, Russia; (A.M.); (D.M.); (Z.A.); (E.A.); (O.G.); (P.V.)
| | - Denis Maksimov
- Moscow Center for Advanced Studies, Kulakova Str. 20, Moscow 123592, Russia; (A.M.); (D.M.); (Z.A.); (E.A.); (O.G.); (P.V.)
| | - Zoia Antysheva
- Moscow Center for Advanced Studies, Kulakova Str. 20, Moscow 123592, Russia; (A.M.); (D.M.); (Z.A.); (E.A.); (O.G.); (P.V.)
| | - Julia Krupinova
- Moscow Center for Advanced Studies, Kulakova Str. 20, Moscow 123592, Russia; (A.M.); (D.M.); (Z.A.); (E.A.); (O.G.); (P.V.)
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
| | - Ekaterina Avsievich
- Moscow Center for Advanced Studies, Kulakova Str. 20, Moscow 123592, Russia; (A.M.); (D.M.); (Z.A.); (E.A.); (O.G.); (P.V.)
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
| | - Olga Glazova
- Moscow Center for Advanced Studies, Kulakova Str. 20, Moscow 123592, Russia; (A.M.); (D.M.); (Z.A.); (E.A.); (O.G.); (P.V.)
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
| | - Natalia Bodunova
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
| | - Nikolay Karnaukhov
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
| | - Ilia Feidorov
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
| | - Diana Salimgereeva
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
| | - Mark Voloshin
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
| | - Pavel Volchkov
- Moscow Center for Advanced Studies, Kulakova Str. 20, Moscow 123592, Russia; (A.M.); (D.M.); (Z.A.); (E.A.); (O.G.); (P.V.)
- Moscow Clinical Scientific Center N.A. A.S. Loginov, Moscow 111123, Russia; (N.B.); (N.K.); (I.F.); (D.S.); (M.V.)
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Nie Y, Zhang Y, Liu S, Xu Z, Xia C, Du L, Yin X, Wang J. Downregulation of Sirt3 contributes to β-cell dedifferentiation via FoxO1 in type 2 diabetic mellitus. Acta Diabetol 2024; 61:485-494. [PMID: 38150004 DOI: 10.1007/s00592-023-02221-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 11/29/2023] [Indexed: 12/28/2023]
Abstract
AIMS FoxO1 is an important factor in the β-cell differentiation in type 2 diabetes mellitus (T2DM). Sirt3 is found to be involved in FoxO1 function. This study investigated the role of Sirt3 in the β-cell dedifferentiation and its mechanism. METHODS Twelve-week-old db/db mice and INS1 cells transfected with Sirt3-specific short hairpin RNA (shSirt3) were used to evaluate the dedifferentiation of β-cell. Insulin levels were measured by enzyme linked immunosorbent assay. The proteins of Sirt3, T-FoxO1, Ac-FoxO1 and differentiation indexes such as NGN3, OCT4, MAFA were determined by western blot or immunofluorescence staining. The combination of Sirt3 and FoxO1 was determined by the co-immunoprecipitation assay. The transcriptional activity of FoxO1 was detected by dual luciferase reporter assay. RESULTS Both the in vivo and in vitro results showed that Sirt3 was decreased along with β-cell dedifferentiation and decreased function of insulin secretion under high glucose conditions. When Sirt3 was knocked down in INS1 cells, increased β-cell dedifferentiation and lowered insulin secretion were observed. This effect was closely related to the amount loss and the decreased deacetylation of FoxO1, which resulted in a reduction in transcriptional activity. CONCLUSION Downregulation of Sirt3 contributes to β-cell dedifferentiation in high glucose via FoxO1. Intervention of Sirt3 may be an effective approach to prevent β-cell failure in T2DM.
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Affiliation(s)
- Yaxing Nie
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Yunye Zhang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Shuqing Liu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Zhi Xu
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Chunya Xia
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Lei Du
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Xiaoxing Yin
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China
| | - Jianyun Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221002, Jiangsu, China.
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Morisseau L, Tokito F, Poulain S, Plaisance V, Pawlowski V, Kim SH, Legallais C, Jellali R, Sakai Y, Abderrahmani A, Leclerc E. Generation of β-like cell subtypes from differentiated human induced pluripotent stem cells in 3D spheroids. Mol Omics 2023; 19:810-822. [PMID: 37698079 DOI: 10.1039/d3mo00050h] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2023]
Abstract
Since the identification of four different pancreatic β-cell subtypes and bi-hormomal cells playing a role in the diabetes pathogenesis, the search for in vitro models that mimics such cells heterogeneity became a key priority in experimental and clinical diabetology. We investigated the potential of human induced pluripotent stem cells to lead to the development of the different β-cells subtypes in honeycomb microwell-based 3D spheroids. The glucose-stimulated insulin secretion confirmed the spheroids functionality. Then, we performed a single cell RNA sequencing of the spheroids. Using a knowledge-based analysis with a stringency on the pancreatic markers, we extracted the β-cells INS+/UCN3+ subtype (11%; β1-like cells), the INS+/ST8SIA1+/CD9- subtype (3%, β3-like cells) and INS+/CD9+/ST8SIA1-subtype (1%; β2-like cells) consistently with literature findings. We did not detect the INS+/ST8SIA1+/CD9+ cells (β4-like cells). Then, we also identified four bi-hormonal cells subpopulations including δ-like cells (INS+/SST+, 6%), γ-like cells (INS+/PPY+, 3%), α-like-cells (INS+/GCG+, 6%) and ε-like-cells (INS+/GHRL+, 2%). Using data-driven clustering, we extracted four progenitors' subpopulations (with the lower level of INS gene) that included one population highly expressing inhibin genes (INHBA+/INHBB+), one population highly expressing KCNJ3+/TPH1+, one population expressing hepatocyte-like lineage markers (HNF1A+/AFP+), and one population expressing stem-like cell pancreatic progenitor markers (SOX2+/NEUROG3+). Furthermore, among the cycling population we found a large number of REST+ cells and CD9+ cells (CD9+/SPARC+/REST+). Our data confirm that our differentiation leads to large β-cell heterogeneity, which can be used for investigating β-cells plasticity under physiological and pathophysiological conditions.
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Affiliation(s)
- Lisa Morisseau
- Biomechanics and Bioengineering UMR 7338, Université de technologie de Compiègne, CNRS, Centre de Recherche Royallieu CS 60319, Compiègne, 60203 Cedex, France
| | - Fumiya Tokito
- Department of Chemical System Engineering, Graduate School of Engineering, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
| | - Stéphane Poulain
- Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba; Meguro-ku, Tokyo, 153-8505, Japan
| | - Valerie Plaisance
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520, IEMN, F-59000 Lille, France
| | - Valerie Pawlowski
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520, IEMN, F-59000 Lille, France
| | - Soo Hyeon Kim
- Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba; Meguro-ku, Tokyo, 153-8505, Japan
| | - Cécile Legallais
- Biomechanics and Bioengineering UMR 7338, Université de technologie de Compiègne, CNRS, Centre de Recherche Royallieu CS 60319, Compiègne, 60203 Cedex, France
| | - Rachid Jellali
- Biomechanics and Bioengineering UMR 7338, Université de technologie de Compiègne, CNRS, Centre de Recherche Royallieu CS 60319, Compiègne, 60203 Cedex, France
| | - Yasuyuki Sakai
- Department of Chemical System Engineering, Graduate School of Engineering, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
- Laboratory for Integrated Micro Mechatronic Systems, CNRS/IIS IRL 2820, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba; Meguro-ku, Tokyo, 153-8505, Japan
| | - Amar Abderrahmani
- Univ. Lille, CNRS, Centrale Lille, Univ. Polytechnique Hauts-de-France, UMR 8520, IEMN, F-59000 Lille, France
| | - Eric Leclerc
- Laboratory for Integrated Micro Mechatronic Systems, CNRS/IIS IRL 2820, Institute of Industrial Science, University of Tokyo, 4-6-1 Komaba; Meguro-ku, Tokyo, 153-8505, Japan
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Zhang W, Xu Y, Wang X, Oikawa T, Su G, Wauthier E, Wu G, Sethupathy P, He Z, Liu J, Reid LM. Fibrolamellar carcinomas-growth arrested by paracrine signals complexed with synthesized 3-O sulfated heparan sulfate oligosaccharides. Matrix Biol 2023; 121:194-216. [PMID: 37402431 DOI: 10.1016/j.matbio.2023.06.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/30/2023] [Accepted: 06/28/2023] [Indexed: 07/06/2023]
Abstract
Fibrolamellar carcinomas (FLCs), lethal tumors occurring in children to young adults, have genetic signatures implicating derivation from biliary tree stem cell (BTSC) subpopulations, co-hepato/pancreatic stem cells, involved in hepatic and pancreatic regeneration. FLCs and BTSCs express pluripotency genes, endodermal transcription factors, and stem cell surface, cytoplasmic and proliferation biomarkers. The FLC-PDX model, FLC-TD-2010, is driven ex vivo to express pancreatic acinar traits, hypothesized responsible for this model's propensity for enzymatic degradation of cultures. A stable ex vivo model of FLC-TD-2010 was achieved using organoids in serum-free Kubota's Medium (KM) supplemented with 0.1% hyaluronans (KM/HA). Heparins (10 ng/ml) caused slow expansion of organoids with doubling times of ∼7-9 days. Spheroids, organoids depleted of mesenchymal cells, survived indefinitely in KM/HA in a state of growth arrest for more than 2 months. Expansion was restored with FLCs co-cultured with mesenchymal cell precursors in a ratio of 3:7, implicating paracrine signaling. Signals identified included FGFs, VEGFs, EGFs, Wnts, and others, produced by associated stellate and endothelial cell precursors. Fifty-three, unique heparan sulfate (HS) oligosaccharides were synthesized, assessed for formation of high affinity complexes with paracrine signals, and each complex screened for biological activity(ies) on organoids. Ten distinct HS-oligosaccharides, all 10-12 mers or larger, and in specific paracrine signal complexes elicited particular biological responses. Of note, complexes of paracrine signals and 3-O sulfated HS-oligosaccharides elicited slowed growth, and with Wnt3a, elicited growth arrest of organoids for months. If future efforts are used to prepare HS-oligosaccharides resistant to breakdown in vivo, then [paracrine signal-HS-oligosaccharide] complexes are potential therapeutic agents for clinical treatments of FLCs, an exciting prospect for a deadly disease.
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Affiliation(s)
- Wencheng Zhang
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, United States; Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai 200123, China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
| | - Yongmei Xu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, United States; Glycan Therapeutics Corporation, 617 Hutton Street, Raleigh, NC 27606, United States
| | - Xicheng Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai 200123, China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
| | - Tsunekazu Oikawa
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, United States
| | - Guowei Su
- Glycan Therapeutics Corporation, 617 Hutton Street, Raleigh, NC 27606, United States
| | - Eliane Wauthier
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, United States
| | - Guoxiu Wu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai 200123, China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
| | - Praveen Sethupathy
- Division of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, United States
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, Shanghai 200123, China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China
| | - Jian Liu
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, United States; Glycan Therapeutics Corporation, 617 Hutton Street, Raleigh, NC 27606, United States
| | - Lola M Reid
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, United States; Program in Molecular Biology and Biotechnology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, United States.
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8
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Zhang W, Wang X, Lanzoni G, Wauthier E, Simpson S, Ezzell JA, Allen A, Suitt C, Krolik J, Jhirad A, Dominguez-Bendala J, Cardinale V, Alvaro D, Overi D, Gaudio E, Sethupathy P, Carpino G, Adin C, Piedrahita JA, Mathews K, He Z, Reid LM. A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans. NPJ Regen Med 2023; 8:40. [PMID: 37528116 PMCID: PMC10394089 DOI: 10.1038/s41536-023-00303-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/23/2023] [Indexed: 08/03/2023] Open
Abstract
A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner's Glands in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adulthood. These stem/progenitors in vivo in pigs are in highest numbers in Brunner's Glands and in PDGs nearest the duodenum, and in humans are in Brunner's Glands and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors. Stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on correlation, hierarchical clustering, differential gene expression and principal component analyses (PCA). Gene expression includes representative traits of pluripotency genes (SOX2, OCT4), endodermal transcription factors (e.g. SOX9, SOX17, PDX1), other stem cell traits (e.g. NCAM, CD44, sodium iodide symporter or NIS), and proliferation biomarkers (Ki67). Hepato/pancreatic multipotentiality was demonstrated by the stem/progenitors' responses under distinct ex vivo conditions or in vivo when patch grafted as organoids onto the liver versus the pancreas. Therefore, pigs are logical hosts for translational/preclinical studies for cell therapies with these stem/progenitors for hepatic and pancreatic dysfunctions.
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Affiliation(s)
- Wencheng Zhang
- Department of Cell Biology and Physiology, University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, 27599, USA
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, 200123, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, 200335, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, 200120, Shanghai, China
| | - Xicheng Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, 200123, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, 200335, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, 200120, Shanghai, China
| | - Giacomo Lanzoni
- Diabetes Research Institute, Leonard Miller School of Medicine, 1450 N.W. 10th Avenue, Miami, FL, 33136, USA
| | - Eliane Wauthier
- Department of Cell Biology and Physiology, University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, 27599, USA
| | - Sean Simpson
- Department of Molecular Biomedical Sciences, North Carolina State University (NCSU) College of Veterinary Medicine, Raleigh, NC, 27606, USA
- Comparative Medicine Institute, NCSU, Raleigh, NC, 27606, USA
| | - Jennifer Ashley Ezzell
- Department of Cell Biology and Physiology, University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, 27599, USA
| | - Amanda Allen
- Department of Cell Biology and Physiology, University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, 27599, USA
| | - Carolyn Suitt
- Center for Gastrointestinal Biology and Disease (CGIBD), UNC School of Medicine, Chapel Hill, NC, 27599, USA
| | - Jonah Krolik
- Department of Cell Biology and Physiology, University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, 27599, USA
| | - Alexander Jhirad
- Department of Cell Biology and Physiology, University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, 27599, USA
| | - Juan Dominguez-Bendala
- Diabetes Research Institute, Leonard Miller School of Medicine, 1450 N.W. 10th Avenue, Miami, FL, 33136, USA
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Rome, Latina, 04100, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University, Rome, 00185, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, Rome, 00161, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, Rome, 00161, Italy
| | - Praveen Sethupathy
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, NY, 14853, USA.
| | - Guido Carpino
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, Rome, 00161, Italy.
| | - Christopher Adin
- Department of Clinical Sciences, Soft Tissue and Oncologic Surgery Service, College of Veterinary Medicine, NCSU, Raleigh, NC, 27606, USA.
- Department of Small Animal Clinical Sciences, University of Florida College of Veterinary Medicine, Gainesville, FL, 32608, USA.
| | - Jorge A Piedrahita
- Department of Molecular Biomedical Sciences, North Carolina State University (NCSU) College of Veterinary Medicine, Raleigh, NC, 27606, USA.
- Comparative Medicine Institute, NCSU, Raleigh, NC, 27606, USA.
| | - Kyle Mathews
- Department of Clinical Sciences, Soft Tissue and Oncologic Surgery Service, College of Veterinary Medicine, NCSU, Raleigh, NC, 27606, USA.
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, 200123, Shanghai, China.
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, 200335, Shanghai, China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, 200120, Shanghai, China.
| | - Lola McAdams Reid
- Department of Cell Biology and Physiology, University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, 27599, USA.
- Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA.
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9
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Zhang W, Cui Y, Du Y, Yang Y, Fang T, Lu F, Kong W, Xiao C, Shi J, Reid LM, He Z. Liver cell therapies: cellular sources and grafting strategies. Front Med 2023; 17:432-457. [PMID: 37402953 DOI: 10.1007/s11684-023-1002-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 04/27/2023] [Indexed: 07/06/2023]
Abstract
The liver has a complex cellular composition and a remarkable regenerative capacity. The primary cell types in the liver are two parenchymal cell populations, hepatocytes and cholangiocytes, that perform most of the functions of the liver and that are helped through interactions with non-parenchymal cell types comprising stellate cells, endothelia and various hemopoietic cell populations. The regulation of the cells in the liver is mediated by an insoluble complex of proteins and carbohydrates, the extracellular matrix, working synergistically with soluble paracrine and systemic signals. In recent years, with the rapid development of genetic sequencing technologies, research on the liver's cellular composition and its regulatory mechanisms during various conditions has been extensively explored. Meanwhile breakthroughs in strategies for cell transplantation are enabling a future in which there can be a rescue of patients with end-stage liver diseases, offering potential solutions to the chronic shortage of livers and alternatives to liver transplantation. This review will focus on the cellular mechanisms of liver homeostasis and how to select ideal sources of cells to be transplanted to achieve liver regeneration and repair. Recent advances are summarized for promoting the treatment of end-stage liver diseases by forms of cell transplantation that now include grafting strategies.
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Affiliation(s)
- Wencheng Zhang
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Yangyang Cui
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
- Postgraduate Training Base of Shanghai East Hospital, Jinzhou Medical University, Jinzhou, 121001, China
| | - Yuan Du
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Yong Yang
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Ting Fang
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Fengfeng Lu
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China
| | - Weixia Kong
- Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Canjun Xiao
- Department of General Surgery, Ji'an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji'an, 343006, China
| | - Jun Shi
- The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
- Department of General Surgery, Ji'an Hospital, Shanghai East Hospital, School of Medicine, Tongji University, Ji'an, 343006, China
| | - Lola M Reid
- Department of Cell Biology and Physiology and Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA.
| | - Zhiying He
- Institute for Regenerative Medicine, Ji'an Hospital, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200123, China.
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, China.
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10
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Seeberger KL, Salama BF, Kelly S, Rosko M, Castro C, DesAulniers J, Korbutt GS. Heterogenous expression of endocrine and progenitor cells within the neonatal porcine pancreatic lobes-Implications for neonatal porcine islet xenotransplantation. Xenotransplantation 2023; 30:e12793. [PMID: 36748727 DOI: 10.1111/xen.12793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 10/21/2022] [Accepted: 01/05/2023] [Indexed: 02/08/2023]
Abstract
Neonatal porcine islets (NPIs) are a source of islets for xenotransplantation. In the pig, the pancreatic lobes remain separate, thus, when optimizing NPI isolation, the pancreatic lobes included in the pancreatic digest should be specified. These lobes are the duodenal (DL), splenic (SL) and connecting (CL) lobe that correspond to the head, body-tail, and uncinate process of the human pancreas. In this study we are the first to evaluate all three neonatal porcine pancreatic lobes and NPIs isolated from these lobes. We report, a significant difference in endocrine and progenitor cell composition between lobes, and observed pancreatic duct glands (PDG) within the mesenchyme surrounding exocrine ducts in the DL and CL. Following in vitro differentiation, NPIs isolated from each lobe differed significantly in the percent increase of endocrine cells and final cell composition. Compared to other recipients, diabetic immunodeficient mice transplanted with NPIs isolated from the SL demonstrated euglycemic control as early as 4 weeks (p < 0.05) and achieved normoglycemia by 6 weeks post-transplant (p < 0.01). For the first time we report significant differences between the neonatal porcine pancreatic lobes and demonstrate that NPIs from these lobes differ in xenograft function.
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Affiliation(s)
- Karen L Seeberger
- Alberta Diabetes Institute and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Bassem F Salama
- Alberta Diabetes Institute and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Sandra Kelly
- Alberta Diabetes Institute and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Mandy Rosko
- Alberta Diabetes Institute and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Chelsea Castro
- Alberta Diabetes Institute and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Jessica DesAulniers
- Alberta Diabetes Institute and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Gregory S Korbutt
- Alberta Diabetes Institute and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.,Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
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11
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Overi D, Carpino G, Moretti M, Franchitto A, Nevi L, Onori P, De Smaele E, Federici L, Santorelli D, Maroder M, Reid LM, Cardinale V, Alvaro D, Gaudio E. Islet Regeneration and Pancreatic Duct Glands in Human and Experimental Diabetes. Front Cell Dev Biol 2022; 10:814165. [PMID: 35186929 PMCID: PMC8855925 DOI: 10.3389/fcell.2022.814165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/10/2022] [Indexed: 11/20/2022] Open
Abstract
Contrasting evidence is present regarding the contribution of stem/progenitor cell populations to pancreatic regeneration in diabetes. Interestingly, a cell compartment with stem/progenitor cell features has been identified in the pancreatic duct glands (PDGs). The aims of the present study were to evaluate pancreatic islet injury and regeneration, and the participation of the PDG compartment in type 2 diabetic mellitus (T2DM) and in an experimental model of diabetes. Human pancreata were obtained from normal (N = 5) or T2DM (N = 10) cadaveric organ donors. Experimental diabetes was generated in mice by intraperitoneal injection of 150 mg/kg of streptozotocin (STZ, N = 10); N = 10 STZ mice also received daily intraperitoneal injections of 100 µg of human recombinant PDX1 peptide (STZ + PDX1). Samples were examined by immunohistochemistry/immunofluorescence or RT-qPCR. Serum glucose and c-peptide levels were measured in mice. Islets in T2DM patients showed β-cell loss, signs of injury and proliferation, and a higher proportion of central islets. PDGs in T2DM patients had a higher percentage of proliferating and insulin+ or glucagon+ cells compared to controls; pancreatic islets could be observed within pancreatic duct walls of T2DM patients. STZ mice were characterized by reduced islet area compared to controls. PDX1 treatment increased islet area and the percentage of central islets compared to untreated STZ mice but did not revert diabetes. In conclusion, T2DM patients show signs of pancreatic islet regeneration and involvement of the PDG niche. PDX1 administration could support increased endocrine pancreatic regeneration in STZ. These findings contribute to defining the role and participation of stem/progenitor cell compartments within the pancreas.
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Affiliation(s)
- Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome “Foro Italico”, Rome, Italy
- *Correspondence: Guido Carpino,
| | - Marta Moretti
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Lorenzo Nevi
- Department of Biosciences, University of Milan, Milan, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Enrico De Smaele
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Luca Federici
- CAST Center for Advanced Studies and Technology and Department of Innovative Technologies in Medicine and Odontoiatry, University “G. D’Annunzio” of Chieti-Pescara, Chieti, Italy
| | - Daniele Santorelli
- Department of Biochemical Sciences “Rossi Fanelli”, Sapienza University of Rome, Rome, Italy
| | - Marella Maroder
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Lola M. Reid
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
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12
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Cable J, Pei D, Reid LM, Wang XW, Bhatia S, Karras P, Melenhorst JJ, Grompe M, Lathia JD, Song E, Kuo CJ, Zhang N, White RM, Ma SK, Ma L, Chin YR, Shen MM, Ng IOL, Kaestner KH, Zhou L, Sikandar S, Schmitt CA, Guo W, Wong CCL, Ji J, Tang DG, Dubrovska A, Yang C, Wiedemeyer WR, Weissman IL. Cancer stem cells: advances in biology and clinical translation-a Keystone Symposia report. Ann N Y Acad Sci 2021; 1506:142-163. [PMID: 34850398 PMCID: PMC9153245 DOI: 10.1111/nyas.14719] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 12/16/2022]
Abstract
The test for the cancer stem cell (CSC) hypothesis is to find a target expressed on all, and only CSCs in a patient tumor, then eliminate all cells with that target that eliminates the cancer. That test has not yet been achieved, but CSC diagnostics and targets found on CSCs and some other cells have resulted in a few clinically relevant therapies. However, it has become apparent that eliminating the subset of tumor cells characterized by self-renewal properties is essential for long-term tumor control. CSCs are able to regenerate and initiate tumor growth, recapitulating the heterogeneity present in the tumor before treatment. As great progress has been made in identifying and elucidating the biology of CSCs as well as their interactions with the tumor microenvironment, the time seems ripe for novel therapeutic strategies that target CSCs to find clinical applicability. On May 19-21, 2021, researchers in cancer stem cells met virtually for the Keystone eSymposium "Cancer Stem Cells: Advances in Biology and Clinical Translation" to discuss recent advances in the understanding of CSCs as well as clinical efforts to target these populations.
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Affiliation(s)
| | - Duanqing Pei
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou, China
| | - Lola M Reid
- Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, and Liver Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sonam Bhatia
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York
| | - Panagiotis Karras
- Laboratory for Molecular Cancer Biology, Center for Cancer Biology and Laboratory for Molecular Cancer Biology, Department of Oncology, Leuven, Belgium
| | - Jan Joseph Melenhorst
- Glioblastoma Translational Center of Excellence, The Abramson Cancer Center and Department of Pathology & Laboratory Medicine, Perelman School of Medicine and Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Markus Grompe
- Department of Molecular and Medical Genetics, Department of Pediatrics, and Oregon Stem Cell Center, Oregon Health & Science University, Portland, Oregon
| | - Justin D Lathia
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center and Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Bioland Laboratory; Program of Molecular Medicine, Zhongshan School of Medicine, Sun Yat-Sen University; and Fountain-Valley Institute for Life Sciences, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Calvin J Kuo
- Division of Hematology, Department of Medicine, Stanford University, Stanford, California
| | - Ning Zhang
- Translational Cancer Research Center, Peking University First Hospital, Beijing, China
| | - Richard M White
- Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Stephanie Ky Ma
- School of Biomedical Sciences and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Lichun Ma
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Y Rebecca Chin
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China
| | - Michael M Shen
- Departments of Medicine, Genetics and Development, Urology, and Systems Biology, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York
| | - Irene Oi Lin Ng
- Department of Pathology and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Klaus H Kaestner
- Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lei Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, Hong Kong
| | - Shaheen Sikandar
- Institute for the Biology of Stem Cells, University of California, Santa Cruz, Santa Cruz, California
| | - Clemens A Schmitt
- Charité - Universitätsmedizin Berlin, Hematology/Oncology, and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany, and Johannes Kepler University, Kepler Universitätsklinikum, Hematology/Oncology, Linz, Austria
| | - Wei Guo
- Department of Biology, School of Arts & Sciences, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carmen Chak-Lui Wong
- Department of Pathology and State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
| | - Junfang Ji
- MOE Key Laboratory of Biosystems Homeostasis & Protection, and Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Dean G Tang
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, and Experimental Therapeutics (ET) Graduate Program, University at Buffalo, Buffalo, New York
| | - Anna Dubrovska
- OncoRay National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, Heidelberg, Germany
| | - Chunzhang Yang
- Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland
| | | | - Irving L Weissman
- Institute for Stem Cell Biology and Regenerative Medicine, Ludwig Center for Cancer Stem Cell Research, Stanford University, Stanford, California
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13
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Zhang W, Lanzoni G, Hani H, Overi D, Cardinale V, Simpson S, Pitman W, Allen A, Yi X, Wang X, Gerber D, Prestwich G, Lozoya O, Gaudio E, Alvaro D, Tokaz D, Dominguez-Bendala J, Adin C, Piedrahita J, Mathews K, Sethupathy P, Carpino G, He Z, Wauthier E, Reid LM. Patch grafting, strategies for transplantation of organoids into solid organs such as liver. Biomaterials 2021; 277:121067. [PMID: 34517276 DOI: 10.1016/j.biomaterials.2021.121067] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 08/06/2021] [Accepted: 08/08/2021] [Indexed: 12/28/2022]
Abstract
Epithelial cell therapies have been at an impasse because of inefficient methods of transplantation to solid organs. Patch grafting strategies were established enabling transplantation of ≥107th organoids/patch of porcine GFP+ biliary tree stem/progenitors into livers of wild type hosts. Grafts consisted of organoids embedded in soft (~100 Pa) hyaluronan hydrogels, both prepared in serum-free Kubota's Medium; placed against target sites; covered with a silk backing impregnated with more rigid hyaluronan hydrogels (~700 Pa); and use of the backing to tether grafts with sutures or glue to target sites. Hyaluronan coatings (~200-300 Pa) onto the serosal surface of the graft served to minimize adhesions with neighboring organs. The organ's clearance of hyaluronans enabled restoration of tissue-specific paracrine and systemic signaling, resulting in return of normal hepatic histology, with donor parenchymal cells uniformly integrated amidst host cells and that had differentiated to mature hepatocytes and cholangiocytes. Grafts containing donor mature hepatocytes, partnered with endothelia, and in the same graft biomaterials as for stem/progenitor organoids, did not engraft. Engraftment occurred if porcine liver-derived mesenchymal stem cells (MSCs) were co-transplanted with donor mature cells. RNA-seq analyses revealed that engraftment correlated with expression of matrix-metalloproteinases (MMPs), especially secreted isoforms that were found expressed strongly by organoids, less so by MSCs, and minimally, if at all, by adult cells. Engraftment with patch grafting strategies occurred without evidence of emboli or ectopic cell distribution. It was successful with stem/progenitor organoids or with cells with a source(s) of secreted MMP isoforms and offers significant potential for enabling cell therapies for solid organs.
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Affiliation(s)
- Wencheng Zhang
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA; Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, 1800 Yuntai Rd, Pudong New Area, Shanghai, 200123, China
| | - Giacomo Lanzoni
- Diabetes Research Institute, U. Miami Leonard M. Miller School of Medicine, 1450 N.W. 10th Avenue, Miami, FL, 33136, USA
| | - Homayoun Hani
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, Piazzale Aldo Moro, 5, 00185, Roma RM, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Piazzale Aldo Moro, 5, 00185, Roma RM, Italy
| | - Sean Simpson
- Department of Molecular Biomedical Sciences, NCSU Colleage of Veterinary Medicine, Raleigh, NC, 27606, USA; The Comparative Medicine Institute, NCSU College of Veterinary Medicine, Raleigh, NC, 27606, USA; Department of Comparative Veterinary Anatomy, NCSU College of Veterinary Medicine, Raleigh, NC, 27606, USA
| | - Wendy Pitman
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, T7 006D Veterinary Research Tower, Box 17, Ithaca, NY, 14853, USA
| | - Amanda Allen
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA
| | - Xianwen Yi
- Departments of Surgery, UNC School of Medicine, Chapel Hill, NC, 27599, USA
| | - Xicheng Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, 1800 Yuntai Rd, Pudong New Area, Shanghai, 200123, China
| | - David Gerber
- Departments of Surgery, UNC School of Medicine, Chapel Hill, NC, 27599, USA
| | - Glenn Prestwich
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, 84112, USA
| | - Oswaldo Lozoya
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA; Department of Biomedical Engineering, UNC School of Medicine, Chapel Hill, NC, 27599, USA.
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University, Piazzale Aldo Moro, 5, 00185, Roma RM, Italy
| | - Domenico Alvaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Piazzale Aldo Moro, 5, 00185, Roma RM, Italy
| | - Debra Tokaz
- Department of Population Health and Pathobiology, NCSU College of Veterinary Medicine, Raleigh, NC, 27606, USA
| | - Juan Dominguez-Bendala
- Diabetes Research Institute, U. Miami Leonard M. Miller School of Medicine, 1450 N.W. 10th Avenue, Miami, FL, 33136, USA
| | - Christopher Adin
- Department of Clinical Sciences, NCSU College of Veterinary Medicine, Raleigh, NC, 27606, USA
| | - Jorge Piedrahita
- Department of Molecular Biomedical Sciences, NCSU Colleage of Veterinary Medicine, Raleigh, NC, 27606, USA; The Comparative Medicine Institute, NCSU College of Veterinary Medicine, Raleigh, NC, 27606, USA; Department of Comparative Veterinary Anatomy, NCSU College of Veterinary Medicine, Raleigh, NC, 27606, USA
| | - Kyle Mathews
- Department of Clinical Sciences, NCSU College of Veterinary Medicine, Raleigh, NC, 27606, USA
| | - Praveen Sethupathy
- Department of Biomedical Sciences, Cornell University College of Veterinary Medicine, T7 006D Veterinary Research Tower, Box 17, Ithaca, NY, 14853, USA
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Roma, Italy
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University School of Medicine, 1800 Yuntai Rd, Pudong New Area, Shanghai, 200123, China
| | - Eliane Wauthier
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA
| | - Lola M Reid
- Departments of Cell Biology and Physiology, Program in Molecular Biology and Biotechnology, UNC School of Medicine, Chapel Hill, NC, 27599, USA.
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14
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Yong HJ, Xie G, Liu C, Wang W, Naji A, Irianto J, Wang YJ. Gene Signatures of NEUROGENIN3+ Endocrine Progenitor Cells in the Human Pancreas. Front Endocrinol (Lausanne) 2021; 12:736286. [PMID: 34566896 PMCID: PMC8456125 DOI: 10.3389/fendo.2021.736286] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
NEUROGENIN3+ (NEUROG3+) cells are considered to be pancreatic endocrine progenitors. Our current knowledge on the molecular program of NEUROG3+ cells in humans is largely extrapolated from studies in mice. We hypothesized that single-cell RNA-seq enables in-depth exploration of the rare NEUROG3+ cells directly in humans. We aligned four large single-cell RNA-seq datasets from postnatal human pancreas. Our integrated analysis revealed 10 NEUROG3+ epithelial cells from a total of 11,174 pancreatic cells. Noticeably, human NEUROG3+ cells clustered with mature pancreatic cells and epsilon cells displayed the highest frequency of NEUROG3 positivity. We confirmed the co-expression of NEUROG3 with endocrine markers and the high percentage of NEUROG3+ cells among epsilon cells at the protein level based on immunostaining on pancreatic tissue sections. We further identified unique genetic signatures of the NEUROG3+ cells. Regulatory network inference revealed novel transcription factors including Prospero homeobox protein 1 (PROX1) may act jointly with NEUROG3. As NEUROG3 plays a central role in endocrine differentiation, knowledge gained from our study will accelerate the development of beta cell regeneration therapies to treat diabetes.
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Affiliation(s)
- Hyo Jeong Yong
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States
| | - Gengqiang Xie
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States
| | - Chengyang Liu
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, United States
| | - Wei Wang
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, United States
| | - Ali Naji
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, United States
| | - Jerome Irianto
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States
| | - Yue J. Wang
- Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, United States
- *Correspondence: Yue J. Wang,
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15
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Pamphlett R, Colebatch AJ, Doble PA, Bishop DP. Mercury in Pancreatic Cells of People with and without Pancreatic Cancer. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17238990. [PMID: 33276658 PMCID: PMC7731371 DOI: 10.3390/ijerph17238990] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/27/2020] [Accepted: 11/28/2020] [Indexed: 12/12/2022]
Abstract
Toxic metals have been implicated in the pathogenesis of pancreatic cancer. Human exposure to mercury is widespread, but it is not known how often mercury is present in the human pancreas and which cells might contain mercury. We therefore aimed to determine, in people with and without pancreatic cancer, the distribution and prevalence of mercury in pancreatic cells. Paraffin-embedded sections of normal pancreatic tissue were obtained from pancreatectomy samples of 45 people who had pancreatic adenocarcinoma, and from autopsy samples of 38 people without pancreatic cancer. Mercury was identified using two methods of elemental bio-imaging: (1) With autometallography, inorganic mercury was seen in islet cells in 14 of 30 males (47%) with pancreatic cancer compared to two of 17 males (12%) without pancreatic cancer (p = 0.024), and in 10 of 15 females (67%) with pancreatic cancer compared to four of 21 females (19%) without pancreatic cancer (p = 0.006). Autometallographic mercury was present in acinar cells in 24% and in periductal cells in 11% of people with pancreatic cancer, but not in those without pancreatic cancer. (2) Laser ablation-inductively coupled plasma-mass spectrometry confirmed the presence of mercury in islets that stained with autometallography and detected cadmium, lead, chromium, iron, nickel and aluminium in some samples. In conclusion, the genotoxic metal mercury is found in normal pancreatic cells in more people with, than without, pancreatic cancer. These findings support the hypothesis that toxic metals such as mercury contribute to the pathogenesis of pancreatic cancer.
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Affiliation(s)
- Roger Pamphlett
- Discipline of Pathology, Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney 2050, Australia
- Department of Neuropathology, Royal Prince Alfred Hospital, Sydney 2050, Australia
- Correspondence:
| | - Andrew J. Colebatch
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney 2050, Australia;
| | - Philip A. Doble
- Elemental Bio-Imaging Facility, School of Mathematical and Physical Sciences, University of Technology Sydney, Sydney 2007, Australia; (P.A.D.); (D.P.B.)
| | - David P. Bishop
- Elemental Bio-Imaging Facility, School of Mathematical and Physical Sciences, University of Technology Sydney, Sydney 2007, Australia; (P.A.D.); (D.P.B.)
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16
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Vav1 Sustains the In Vitro Differentiation of Normal and Tumor Precursors to Insulin Producing Cells Induced by all-Trans Retinoic Acid (ATRA). Stem Cell Rev Rep 2020; 17:673-684. [PMID: 33165749 PMCID: PMC8036226 DOI: 10.1007/s12015-020-10074-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2020] [Indexed: 02/07/2023]
Abstract
All-trans retinoic acid (ATRA) promotes the development and the function of insulin producing cells and induces partial differentiation of pancreatic tumor cells. A number of evidences clearly indicate that the ATRA mediated signaling may have a substantial role in therapeutic approaches based on restoration of functional β-cells. Among the proteins up-regulated by ATRA, Vav1 is involved in maturation and function of haematopoietic cells and is essential for retinoids induced differentiation of tumor promyelocytes. The presence of Vav1 in solid tissues, including pancreas, is considered ectopic and no role in the differentiation of human epithelial cells has so far been described. We demonstrated here that Vav1 sustains the maturation to β-cells of the normal precursors human Biliary Tree Stem/progenitor Cells (hBTSCs) induced by a differentiation medium containing ATRA and that, in the mature normal pancreas, insulin-producing cells express variable levels of Vav1. Using pancreatic ductal adenocarcinoma (PDAC)-derived cells, we also revealed that the ATRA induced up-modulation of Vav1 is essential for the retinoid-induced trans-differentiation of neoplastic cells into insulin producing cells. The results of this study identify Vav1 as crucial molecule in ATRA induced maturation of insulin producing cells and suggest this protein as a marker for new strategies ended to restore functional β-cells.
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17
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Carpino G, Del Ben M, Pastori D, Carnevale R, Baratta F, Overi D, Francis H, Cardinale V, Onori P, Safarikia S, Cammisotto V, Alvaro D, Svegliati-Baroni G, Angelico F, Gaudio E, Violi F. Increased Liver Localization of Lipopolysaccharides in Human and Experimental NAFLD. Hepatology 2020; 72:470-485. [PMID: 31808577 DOI: 10.1002/hep.31056] [Citation(s) in RCA: 252] [Impact Index Per Article: 50.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Accepted: 11/13/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Lipopolysaccharides (LPS) is increased in nonalcoholic fatty liver disease (NAFLD), but its relationship with liver inflammation is not defined. APPROACH AND RESULTS We studied Escherichia coli LPS in patients with biopsy-proven NAFLD, 25 simple steatosis (nonalcoholic fatty liver) and 25 nonalcoholic steatohepatitis (NASH), and in mice with diet-induced NASH. NASH patients had higher serum LPS and hepatocytes LPS localization than controls, which was correlated with serum zonulin and phosphorylated nuclear factor-κB expression. Toll-like receptor 4 positive (TLR4+ ) macrophages were higher in NASH than simple steatosis or controls and correlated with serum LPS. NASH biopsies showed a higher CD61+ platelets, and most of them were TLR4+ . TLR4+ platelets correlated with serum LPS values. In mice with NASH, LPS serum levels and LPS hepatocyte localization were increased compared with control mice and associated with nuclear factor-κB activation. Mice on aspirin developed lower fibrosis and extent compared with untreated ones. Treatment with TLR4 inhibitor resulted in lower liver inflammation in mice with NASH. CONCLUSIONS In NAFLD, Escherichia coli LPS may increase liver damage by inducing macrophage and platelet activation through the TLR4 pathway.
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Affiliation(s)
- Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico,", Rome, Italy
| | - Maria Del Ben
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Daniele Pastori
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Roberto Carnevale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- Mediterranea Cardiocentro, Naples, Italy
| | - Francesco Baratta
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Heather Francis
- Indiana Center for Liver Research, Richard L. Roudebush VA Medical Center and Indiana University, Indianapolis, IN
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Samira Safarikia
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Vittoria Cammisotto
- Department of General Surgery and Surgical Specialty Paride Stefanini, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Francesco Violi
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
- Mediterranea Cardiocentro, Naples, Italy
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18
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Chen S, Du K, Zou C. Current progress in stem cell therapy for type 1 diabetes mellitus. Stem Cell Res Ther 2020; 11:275. [PMID: 32641151 PMCID: PMC7346484 DOI: 10.1186/s13287-020-01793-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/19/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is the most common chronic autoimmune disease in young patients and is characterized by the loss of pancreatic β cells; as a result, the body becomes insulin deficient and hyperglycemic. Administration or injection of exogenous insulin cannot mimic the endogenous insulin secreted by a healthy pancreas. Pancreas and islet transplantation have emerged as promising treatments for reconstructing the normal regulation of blood glucose in T1DM patients. However, a critical shortage of pancreases and islets derived from human organ donors, complications associated with transplantations, high cost, and limited procedural availability remain bottlenecks in the widespread application of these strategies. Attempts have been directed to accommodate the increasing population of patients with T1DM. Stem cell therapy holds great potential for curing patients with T1DM. With the advent of research on stem cell therapy for various diseases, breakthroughs in stem cell-based therapy for T1DM have been reported. However, many unsolved issues need to be addressed before stem cell therapy will be clinically feasible for diabetic patients. In this review, we discuss the current research advances in strategies to obtain insulin-producing cells (IPCs) from different precursor cells and in stem cell-based therapies for diabetes.
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Affiliation(s)
- Shuai Chen
- Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Kechen Du
- Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Chunlin Zou
- Key Laboratory of Longevity and Ageing-Related Disease of Chinese Ministry of Education, Center for Translational Medicine and School of Preclinical Medicine, Guangxi Medical University, Nanning, 530021, Guangxi, China.
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19
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Alaimo L, Luciano M, Mohammed D, Versaevel M, Bruyère C, Vercruysse E, Gabriele S. Engineering slit-like channels for studying the growth of epithelial tissues in 3D-confined spaces. Biotechnol Bioeng 2020; 117:2887-2896. [PMID: 32484903 DOI: 10.1002/bit.27446] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/25/2020] [Accepted: 05/31/2020] [Indexed: 01/02/2023]
Abstract
The development of epithelial lumens in ducts is essential to the functioning of various organs and in organogenesis. Ductal elongation requires the collective migration of cell cohorts in three-dimensional (3D) confined spaces, while maintaining their epithelial integrity. Epithelial lumens generally adopt circular morphologies, however abnormalities in complex physiological environments can lead to the narrowing of glandular spaces that adopt elongated and slit-like morphologies. Here, we describe a simple method to form epithelial tissues in microchannels of various widths (100-300 µm) with a constant height of 25 µm that mimic elongated geometries of glandular spaces. The significance of this biomimetic platform has been evidenced by studying the migration of epithelial cell sheets inside these narrow slits of varying dimensions. We show that the growth of epithelial tissues in 3D-confined slits leads to a gradient of cell density along the slit axis and that the migration cell velocity depends on the extent of the spatial confinement. Our findings indicate that nuclear orientation is higher for leader cells and depends on the slit width, whereas YAP protein was predominantly localized in the nucleus of leader cells. This method will pave the way to studies aiming at understanding how 3D-confined spaces, which are reminiscent of in vivo pathological conditions, can affect the growth and the homeostasis of epithelial tissues.
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Affiliation(s)
- Laura Alaimo
- University of Mons, Laboratory for Complex Fluids and Interfaces, Mechanobiology and Soft Matter Group, CIRMAP, Research Institute for Biosciences, Place du Parc, Mons, Belgium
| | - Marine Luciano
- University of Mons, Laboratory for Complex Fluids and Interfaces, Mechanobiology and Soft Matter Group, CIRMAP, Research Institute for Biosciences, Place du Parc, Mons, Belgium
| | - Danahe Mohammed
- University of Mons, Laboratory for Complex Fluids and Interfaces, Mechanobiology and Soft Matter Group, CIRMAP, Research Institute for Biosciences, Place du Parc, Mons, Belgium
| | - Marie Versaevel
- University of Mons, Laboratory for Complex Fluids and Interfaces, Mechanobiology and Soft Matter Group, CIRMAP, Research Institute for Biosciences, Place du Parc, Mons, Belgium
| | - Céline Bruyère
- University of Mons, Laboratory for Complex Fluids and Interfaces, Mechanobiology and Soft Matter Group, CIRMAP, Research Institute for Biosciences, Place du Parc, Mons, Belgium
| | - Eléonore Vercruysse
- University of Mons, Laboratory for Complex Fluids and Interfaces, Mechanobiology and Soft Matter Group, CIRMAP, Research Institute for Biosciences, Place du Parc, Mons, Belgium
| | - Sylvain Gabriele
- University of Mons, Laboratory for Complex Fluids and Interfaces, Mechanobiology and Soft Matter Group, CIRMAP, Research Institute for Biosciences, Place du Parc, Mons, Belgium
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20
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Abstract
The existence of progenitors within pancreatic ducts has been studied for decades, but the hypothesis that they may help regenerate the adult endocrine compartment (chiefly insulin-producing β-cells) remains contentious. Here, we examine the single-cell transcriptome of the human ductal tree. Our data confirm the paradigm-shifting notion that specific lineages, long thought to be cast in stone, are in fact in a state of flux between differentiation stages. In addition to pro-ductal and pro-acinar transcriptomic gradients, our analysis suggests the existence of a third (ducto-endocrine) differentiation axis. Such prediction was experimentally validated by transplanting sorted progenitor-like cells, which revealed their tri-lineage differentiation potential. Our findings further indicate that progenitors might be activated in situ for therapeutic purposes. We have described multipotent progenitor-like cells within the major pancreatic ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3bright+-sorted ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our analysis unveiled the existence of multiple subpopulations along two major axes, one that encompasses a gradient of ductal cell differentiation stages, and another featuring cells with transitional phenotypes toward acinar tissue. A third potential ducto-endocrine axis is revealed upon integration of the ALK3bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1+/ALK3bright+ populations (enriched in PDX1+/ALK3+/CAII− cells) differentiate into all pancreatic lineages, including functional β-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1+/ALK3+/CAII− progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of the duration of the disease. Our findings open the door to the pharmacological activation of progenitor cells in situ.
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21
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Bradney MJ, Venis SM, Yang Y, Konieczny SF, Han B. A Biomimetic Tumor Model of Heterogeneous Invasion in Pancreatic Ductal Adenocarcinoma. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2020; 16:e1905500. [PMID: 31997571 PMCID: PMC7069790 DOI: 10.1002/smll.201905500] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/13/2019] [Indexed: 05/21/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a complex, heterogeneous, and genetically unstable disease. Its tumor microenvironment (TME) is complicated by heterogeneous cancer cell populations and strong desmoplastic stroma. This complex and heterogeneous environment makes it challenging to discover and validate unique therapeutic targets. Reliable and relevant in vitro PDAC tumor models can significantly advance the understanding of the PDAC TME and may enable the discovery and validation of novel drug targets. In this study, an engineered tumor model is developed to mimic the PDAC TME. This biomimetic model, named ductal tumor-microenvironment-on-chip (dT-MOC), permits analysis and experimentation on the epithelial-mesenchymal transition (EMT) and local invasion with intratumoral heterogeneity. This dT-MOC is a microfluidic platform where a duct of murine genetically engineered pancreatic cancer cells is embedded within a collagen matrix. The cancer cells used carry two of the three mutations of KRAS, CDKN2A, and TP53, which are key driver mutations of human PDAC. The intratumoral heterogeneity is mimicked by co-culturing these cancer cells. Using the dT-MOC model, heterogeneous invasion characteristics, and response to transforming growth factor-beta1 are studied. A mechanism of EMT and local invasion caused by the interaction between heterogeneous cancer cell populations is proposed.
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Affiliation(s)
- Michael J Bradney
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, 47907, USA
| | - Stephanie M Venis
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, 47907, USA
| | - Yi Yang
- Department of Biological Science, Purdue University, West Lafayette, IN, 47907, USA
| | - Stephen F Konieczny
- Department of Biological Science, Purdue University, West Lafayette, IN, 47907, USA
| | - Bumsoo Han
- School of Mechanical Engineering, Purdue University, West Lafayette, IN, 47907, USA
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22
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Carpino G, Nevi L, Overi D, Cardinale V, Lu WY, Di Matteo S, Safarikia S, Berloco PB, Venere R, Onori P, Franchitto A, Forbes SJ, Alvaro D, Gaudio E. Peribiliary Gland Niche Participates in Biliary Tree Regeneration in Mouse and in Human Primary Sclerosing Cholangitis. Hepatology 2020; 71:972-989. [PMID: 31330051 DOI: 10.1002/hep.30871] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 07/09/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Mechanisms underlying the repair of extrahepatic biliary tree (EHBT) after injury have been scarcely explored. The aims of this study were to evaluate, by using a lineage tracing approach, the contribution of peribiliary gland (PBG) niche in the regeneration of EHBT after damage and to evaluate, in vivo and in vitro, the signaling pathways involved. APPROACH AND RESULTS Bile duct injury was induced by the administration of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 14 days to Krt19Cre TdTomatoLSL mice. Human biliary tree stem/progenitor cells (BTSC) within PBGs were isolated from EHBT obtained from liver donors. Hepatic duct samples (n = 10) were obtained from patients affected by primary sclerosing cholangitis (PSC). Samples were analyzed by histology, immunohistochemistry, western blotting, and polymerase chain reaction. DDC administration causes hyperplasia of PBGs and periductal fibrosis in EHBT. A PBG cell population (Cytokeratin19- /SOX9+ ) is involved in the renewal of surface epithelium in injured EHBT. The Wnt signaling pathway triggers human BTSC proliferation in vitro and influences PBG hyperplasia in vivo in the DDC-mediated mouse biliary injury model. The Notch signaling pathway activation induces BTSC differentiation in vitro toward mature cholangiocytes and is associated with PBG activation in the DDC model. In human PSC, inflammatory and stromal cells trigger PBG activation through the up-regulation of the Wnt and Notch signaling pathways. CONCLUSIONS We demonstrated the involvement of PBG cells in regenerating the injured biliary epithelium and identified the signaling pathways driving BTSC activation. These results could have relevant implications on the pathophysiology and treatment of cholangiopathies.
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Affiliation(s)
- Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico,", Rome, Italy
| | - Lorenzo Nevi
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Wei-Yu Lu
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, United Kingdom
| | - Sabina Di Matteo
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Samira Safarikia
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Rosanna Venere
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Stuart J Forbes
- Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, United Kingdom
| | - Domenico Alvaro
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
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23
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Franchitto A, Carpino G, Alisi A, De Peppo F, Overi D, De Stefanis C, Romito I, De Vito R, Caccamo R, Sonia B, Alessandra S, Mosca A, Alterio A, Onori P, Gaudio E, Nobili V. The Contribution of the Adipose Tissue-Liver Axis in Pediatric Patients with Nonalcoholic Fatty Liver Disease after Laparoscopic Sleeve Gastrectomy. J Pediatr 2020; 216:117-127.e2. [PMID: 31526528 DOI: 10.1016/j.jpeds.2019.07.037] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 06/16/2019] [Accepted: 07/12/2019] [Indexed: 02/08/2023]
Abstract
OBJECTIVE To evaluate the histopathologic modifications in liver and visceral adipose tissue (VAT), and to correlate these changes with clinical measures, adipokine production, and proinflammatory cytokines in a population of adolescents with obesity with nonalcoholic fatty liver disease (NAFLD) who underwent laparoscopic sleeve gastrectomy (LSG). STUDY DESIGN Twenty adolescents with obesity who underwent LSG and with biopsy-proven NAFLD were included. Patients underwent clinical evaluation and blood tests at baseline and 1 year after the surgical procedure. Liver and VAT specimens were processed for routine histology, immunohistochemistry, and immunofluorescence. RESULTS In adolescents with obesity and NAFLD, hepatic histologic alterations were uncorrelated with VAT inflammation. LSG induced in both liver and VAT tissue histopathology amelioration and macrophage profile modification that were correlated with body mass index and improvement in insulin resistance. The adipokine profile in liver and VAT was associated with weight loss and histologic improvement after LSG. Serum proinflammatory cytokines were correlated with liver and VAT histopathology and IL-1β and IL-6 levels were independently predicted by liver necroinflammatory grade. CONCLUSIONS This study suggests a unique adipose tissue/fatty liver crosstalk in pediatric patients. LSG induces a similar pattern of histologic improvement in the liver and in VAT. Besides VAT, our results strengthen the role of the liver in adipocytokine production and its contribution to systemic inflammation in pediatric patients with NAFLD.
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Affiliation(s)
- Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children Hospital, Rome, Italy
| | - Francesco De Peppo
- Department of Pediatric Surgery, Pediatric Surgery Unit, "Bambino Gesù" Children's Hospital, Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Cristiano De Stefanis
- Histology-Core Facility "Bambino Gesù" Children's Hospital- Institute of Hospitalization and Scientific Care, Rome, Italy
| | - Ilaria Romito
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children Hospital, Rome, Italy
| | - Rita De Vito
- Department of Pathology, Bambino Gesù Children's Hospital, Rome, Italy
| | - Romina Caccamo
- Department of Pediatric Surgery, Pediatric Surgery Unit, "Bambino Gesù" Children's Hospital, Rome, Italy
| | - Battaglia Sonia
- Department of Pediatric Surgery, Pediatric Surgery Unit, "Bambino Gesù" Children's Hospital, Rome, Italy
| | | | - Antonella Mosca
- Hepatology, Gastroenterology and Nutrition Unit - Bambino Gesù Children's Hospital, Rome, Italy.
| | - Arianna Alterio
- Hepatology, Gastroenterology and Nutrition Unit - Bambino Gesù Children's Hospital, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Valerio Nobili
- Hepatology, Gastroenterology and Nutrition Unit - Bambino Gesù Children's Hospital, Rome, Italy; Department of Pediatric - University "La Sapienza", Rome, Italy
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24
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Zaccari P, Cardinale V, Severi C, Pedica F, Carpino G, Gaudio E, Doglioni C, Petrone MC, Alvaro D, Arcidiacono PG, Capurso G. Common features between neoplastic and preneoplastic lesions of the biliary tract and the pancreas. World J Gastroenterol 2019; 25:4343-4359. [PMID: 31496617 PMCID: PMC6710182 DOI: 10.3748/wjg.v25.i31.4343] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 07/13/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
the bile duct system and pancreas show many similarities due to their anatomical proximity and common embryological origin. Consequently, preneoplastic and neoplastic lesions of the bile duct and pancreas share analogies in terms of molecular, histological and pathophysiological features. Intraepithelial neoplasms are reported in biliary tract, as biliary intraepithelial neoplasm (BilIN), and in pancreas, as pancreatic intraepithelial neoplasm (PanIN). Both can evolve to invasive carcinomas, respectively cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). Intraductal papillary neoplasms arise in biliary tract and pancreas. Intraductal papillary neoplasm of the biliary tract (IPNB) share common histologic and phenotypic features such as pancreatobiliary, gastric, intestinal and oncocytic types, and biological behavior with the pancreatic counterpart, the intraductal papillary mucinous neoplasm of the pancreas (IPMN). All these neoplastic lesions exhibit similar immunohistochemical phenotypes, suggesting a common carcinogenic process. Indeed, CCA and PDAC display similar clinic-pathological features as growth pattern, poor response to conventional chemotherapy and radiotherapy and, as a consequence, an unfavorable prognosis. The objective of this review is to discuss similarities and differences between the neoplastic lesions of the pancreas and biliary tract with potential implications on a common origin from similar stem/progenitor cells.
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Affiliation(s)
- Piera Zaccari
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 00161 Rome, Italy
| | - Carola Severi
- Department of Internal Medicine and Medical Specialties, Gastroenterology Unit, Sapienza University of Rome, Rome 00161, Italy
| | - Federica Pedica
- Pathology Department, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome 00161, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Division of Human Anatomy, Sapienza University of Rome, Rome 00161, Italy
| | - Claudio Doglioni
- Pathology Department, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Maria Chiara Petrone
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Domenico Alvaro
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome 00161, Italy
| | - Paolo Giorgio Arcidiacono
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
| | - Gabriele Capurso
- PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, San Raffaele Scientific Institute IRCCS, Milan 20132, Italy
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25
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Functions and the Emerging Role of the Foetal Liver into Regenerative Medicine. Cells 2019; 8:cells8080914. [PMID: 31426422 PMCID: PMC6721721 DOI: 10.3390/cells8080914] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 08/09/2019] [Accepted: 08/12/2019] [Indexed: 12/13/2022] Open
Abstract
During foetal life, the liver plays the important roles of connection and transient hematopoietic function. Foetal liver cells develop in an environment called a hematopoietic stem cell niche composed of several cell types, where stem cells can proliferate and give rise to mature blood cells. Embryologically, at about the third week of gestation, the liver appears, and it grows rapidly from the fifth to 10th week under WNT/β-Catenin signaling pathway stimulation, which induces hepatic progenitor cells proliferation and differentiation into hepatocytes. Development of new strategies and identification of new cell sources should represent the main aim in liver regenerative medicine and cell therapy. Cells isolated from organs with endodermal origin, like the liver, bile ducts, and pancreas, could be preferable cell sources. Furthermore, stem cells isolated from these organs could be more susceptible to differentiate into mature liver cells after transplantation with respect to stem cells isolated from organs or tissues with a different embryological origin. The foetal liver possesses unique features given the co-existence of cells having endodermal and mesenchymal origin, and it could be highly available source candidate for regenerative medicine in both the liver and pancreas. Taking into account these advantages, the foetal liver can be the highest potential and available cell source for cell therapy regarding liver diseases and diabetes.
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26
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Qadir MMF, Álvarez-Cubela S, Klein D, Lanzoni G, García-Santana C, Montalvo A, Pláceres-Uray F, Mazza EMC, Ricordi C, Inverardi LA, Pastori RL, Domínguez-Bendala J. P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics. Cell Rep 2019; 22:2408-2420. [PMID: 29490276 PMCID: PMC5905712 DOI: 10.1016/j.celrep.2018.02.006] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 12/08/2017] [Accepted: 02/01/2018] [Indexed: 12/16/2022] Open
Abstract
Treatment of human pancreatic non-endocrine tissue with Bone Morphogenetic Protein 7 (BMP-7) leads to the formation of glucose-responsive β-like cells. Here, we show that BMP-7 acts on extrainsular cells expressing PDX1 and the BMP receptor activin-like kinase 3 (ALK3/BMPR1A). In vitro lineage tracing indicates that ALK3+ cell populations are multipotent. PDX1+/ALK3+ cells are absent from islets but prominently represented in the major pancreatic ducts and pancreatic duct glands. We identified the purinergic receptor P2Y1 (P2RY1) as a surrogate surface marker for PDX1. Sorted P2RY1+/ALK3bright+ cells form BMP-7-expandable colonies characterized by NKX6.1 and PDX1 expression. Unlike the negative fraction controls, these colonies can be differentiated into multiple pancreatic lineages upon BMP-7 withdrawal. RNA-seq further corroborates the progenitor-like nature of P2RY1+/ALK3bright+ cells and their multilineage differentiation potential. Our studies confirm the existence of progenitor cells in the adult human pancreas and suggest a specific anatomical location within the ductal and glandular networks.
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Affiliation(s)
- Mirza Muhammad Fahd Qadir
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Silvia Álvarez-Cubela
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Dagmar Klein
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Giacomo Lanzoni
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | | | - Abelardo Montalvo
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Fabiola Pláceres-Uray
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | | | - Camillo Ricordi
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Biomedical Engineering, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Luca Alessandro Inverardi
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Division of Metabolism, Endocrinology and Diabetes, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - Ricardo Luis Pastori
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Microbiology & Immunology, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Medicine, Division of Metabolism, Endocrinology and Diabetes, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
| | - Juan Domínguez-Bendala
- Diabetes Research Institute, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA; Department of Surgery, Leonard M. Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
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27
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de Jong IE, Matton AP, van Praagh JB, van Haaften WT, Wiersema‐Buist J, van Wijk LA, Oosterhuis D, Iswandana R, Suriguga S, Overi D, Lisman T, Carpino G, Gouw AS, Olinga P, Gaudio E, Porte RJ. Peribiliary Glands Are Key in Regeneration of the Human Biliary Epithelium After Severe Bile Duct Injury. Hepatology 2019; 69:1719-1734. [PMID: 30506902 PMCID: PMC6594148 DOI: 10.1002/hep.30365] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Accepted: 11/07/2018] [Indexed: 12/22/2022]
Abstract
Peribiliary glands (PBG) are a source of stem/progenitor cells organized in a cellular network encircling large bile ducts. Severe cholangiopathy with loss of luminal biliary epithelium has been proposed to activate PBG, resulting in cell proliferation and differentiation to restore biliary epithelial integrity. However, formal evidence for this concept in human livers is lacking. We therefore developed an ex vivo model using precision-cut slices of extrahepatic human bile ducts obtained from discarded donor livers, providing an intact anatomical organization of cell structures, to study spatiotemporal differentiation and migration of PBG cells after severe biliary injury. Postischemic bile duct slices were incubated in oxygenated culture medium for up to a week. At baseline, severe tissue injury was evident with loss of luminal epithelial lining and mural stroma necrosis. In contrast, PBG remained relatively well preserved and different reactions of PBG were noted, including PBG dilatation, cell proliferation, and maturation. Proliferation of PBG cells increased after 24 hours of oxygenated incubation, reaching a peak after 72 hours. Proliferation of PBG cells was paralleled by a reduction in PBG apoptosis and differentiation from a primitive and pluripotent (homeobox protein Nanog+/ sex-determining region Y-box 9+) to a mature (cystic fibrosis transmembrane conductance regulator+/secretin receptor+) and activated phenotype (increased expression of hypoxia-inducible factor 1 alpha, glucose transporter 1, and vascular endothelial growth factor A). Migration of proliferating PBG cells in our ex vivo model was unorganized, but resulted in generation of epithelial monolayers at stromal surfaces. Conclusion: Human PBG contain biliary progenitor cells and are able to respond to bile duct epithelial loss with proliferation, differentiation, and maturation to restore epithelial integrity. The ex vivo spatiotemporal behavior of human PBG cells provides evidence for a pivotal role of PBG in biliary regeneration after severe injury.
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Affiliation(s)
- Iris E.M. de Jong
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands,Surgical Research Laboratory, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Alix P.M. Matton
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands,Surgical Research Laboratory, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Jasper B. van Praagh
- Surgical Research Laboratory, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands,Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Wouter T. van Haaften
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Janneke Wiersema‐Buist
- Surgical Research Laboratory, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Louise A. van Wijk
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Dorenda Oosterhuis
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Raditya Iswandana
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands,Faculty of PharmacyUniversitas IndonesiaIndonesia
| | - Su Suriguga
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic SciencesSapienza University of RomeRomeItaly
| | - Ton Lisman
- Surgical Research Laboratory, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Guido Carpino
- Division of Health Sciences, Department of Movement, Human and Health SciencesUniversity of Rome “Foro Italico”RomeItaly
| | - Annette S.H. Gouw
- Department of PathologyUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and BiopharmacyUniversity of GroningenGroningenthe Netherlands
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic SciencesSapienza University of RomeRomeItaly
| | - Robert J. Porte
- Section of Hepatobiliary Surgery and Liver Transplantation, Department of SurgeryUniversity of Groningen, University Medical Center GroningenGroningenthe Netherlands
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28
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Farley AM, Braxton DR, Li J, Trounson K, Sakar-Dey S, Nayer B, Ikeda T, Lau KX, Hardikar W, Hasegawa K, Pera MF. Antibodies to a CA 19-9 Related Antigen Complex Identify SOX9 Expressing Progenitor Cells In Human Foetal Pancreas and Pancreatic Adenocarcinoma. Sci Rep 2019; 9:2876. [PMID: 30814526 PMCID: PMC6393509 DOI: 10.1038/s41598-019-38988-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 01/11/2019] [Indexed: 12/21/2022] Open
Abstract
The Sialyl Lewis A antigen, or CA 19-9, is the prototype serum biomarker for adenocarcinoma of the pancreas. Despite extensive clinical study of CA 19-9 in gastrointestinal malignancies, surprisingly little is known concerning the specific cell types that express this marker during development, tissue regeneration and neoplasia. SOX9 is a transcription factor that plays a key role in these processes in foregut tissues. We report the biochemistry and tissue expression of the GCTM-5 antigen, a pancreatic cancer marker related to, but distinct from, CA19-9. This antigen, defined by two monoclonal antibodies recognising separate epitopes on a large glycoconjugate protein complex, is co-expressed with SOX9 by foregut ductal progenitors in the developing human liver and pancreas, and in pancreatic adenocarcinoma. These progenitors are distinct from cell populations identified by DCLK1, LGR5, or canonical markers of liver and pancreatic progenitor cells. Co-expression of this antigen complex and SOX9 also characterises the ductal metaplasia of submucosal glands that occurs during the development of Barrett’s oesophagus. The GCTM-5 antigen complex can be detected in the sera of patients with pancreatic adenocarcinoma. The GCTM-5 epitope shows a much more restricted pattern of expression in the normal adult pancreas relative to CA19-9. Our findings will aid in the identification, characterisation, and monitoring of ductal progenitor cells during development and progression of pancreatic adenocarcinoma in man.
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Affiliation(s)
- Alison M Farley
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia.,The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - David R Braxton
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jonathan Li
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | - Karl Trounson
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | | | - Bhavana Nayer
- Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India
| | - Tatsuhiko Ikeda
- Institute for Integrated Cell-Materials Science, Kyoto University, Kyoto, Japan
| | - Kevin X Lau
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | - Winita Hardikar
- Royal Childrens Hospital, Parkville, Victoria, Australia.,Childrens Medical Research Institute, Parkville, Victoria, Australia
| | - Kouichi Hasegawa
- Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India.,Institute for Integrated Cell-Materials Science, Kyoto University, Kyoto, Japan
| | - Martin F Pera
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia. .,Florey Neuroscience and Mental Health Institute, Parkville, Victoria, Australia. .,The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
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29
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Domínguez-Bendala J, Qadir MMF, Pastori RL. Pancreatic Progenitors: There and Back Again. Trends Endocrinol Metab 2019; 30:4-11. [PMID: 30502039 PMCID: PMC6354578 DOI: 10.1016/j.tem.2018.10.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 10/22/2018] [Accepted: 10/23/2018] [Indexed: 02/06/2023]
Abstract
Adult pancreatic regeneration is one of the most contentious topics in modern biology. The long-held view that the islets of Langerhans can be replenished throughout adult life through the reactivation of ductal progenitor cells has been replaced over the past decade by the now prevailing notion that regeneration does not involve progenitors and occurs only through the duplication of pre-existing mature cells. Here we dissect the limitations of lineage tracing (LT) to draw categorical conclusions about pancreatic regeneration, especially in view of emerging evidence that traditional lineages are less homogeneous and cell fates more dynamic than previously thought. This new evidence further suggests that the two competing hypotheses about regeneration are not mutually exclusive.
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Affiliation(s)
- Juan Domínguez-Bendala
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
| | - Mirza Muhammad Fahd Qadir
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Ricardo Luis Pastori
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA; Department of Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
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30
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Functional Maturation and In Vitro Differentiation of Neonatal Porcine Islet Grafts. Transplantation 2018; 102:e413-e423. [DOI: 10.1097/tp.0000000000002354] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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31
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Ghurburrun E, Borbath I, Lemaigre FP, Jacquemin P. Liver and Pancreas: Do Similar Embryonic Development and Tissue Organization Lead to Similar Mechanisms of Tumorigenesis? Gene Expr 2018; 18:149-155. [PMID: 29580319 PMCID: PMC6190115 DOI: 10.3727/105221618x15216414278706] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The liver and pancreas are closely associated organs that share a common embryological origin. They display amphicrine properties and have similar exocrine organization with parenchymal cells, namely, hepatocytes and acinar cells, secreting bile and pancreatic juice into the duodenum via a converging network of bile ducts and pancreatic ducts. Here we compare and highlight the similarities of molecular mechanisms leading to liver and pancreatic cancer development. We suggest that unraveling tumor development in an organ may provide insight into our understanding of carcinogenesis in the other organ.
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Affiliation(s)
- Elsa Ghurburrun
- *Université catholique de Louvain, de Duve Institute, Brussels, Belgium
| | - Ivan Borbath
- †Université catholique de Louvain, Department of Hepato-Gastro-Enterology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | | | - Patrick Jacquemin
- *Université catholique de Louvain, de Duve Institute, Brussels, Belgium
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32
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Nobili V, Carpino G, De Peppo F, Caccamo R, Mosca A, Romito I, Overi D, Franchitto A, Onori P, Alisi A, Gaudio E. Laparoscopic Sleeve Gastrectomy Improves Nonalcoholic Fatty Liver Disease-Related Liver Damage in Adolescents by Reshaping Cellular Interactions and Hepatic Adipocytokine Production. J Pediatr 2018; 194:100-108.e3. [PMID: 29198531 DOI: 10.1016/j.jpeds.2017.10.036] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/08/2017] [Accepted: 10/13/2017] [Indexed: 02/07/2023]
Abstract
OBJECTIVES To investigate whether the modulation of local cellular cross-talks and the modification of hepatic adipocytokine expression could mechanistically explain the improvement of liver histopathology after laparoscopic sleeve gastrectomy (LSG) in adolescents with nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN Twenty obese (body mass index of ≥35 kg/m2) adolescents who underwent LSG and with biopsy-proven NAFLD were included. At baseline (T0) and 1 year after treatment, patients underwent clinical evaluation, blood tests, and liver biopsy. Hepatic progenitor cells, hepatic stellate cells (HSCs), macrophages, and adipocytokines were evaluated by immunohistochemistry and immunofluorescence. RESULTS Liver biopsy samples after LSG demonstrated a significant improvement of NAFLD Activity Score and fibrosis. Immunohistochemistry indicated a significant reduction of hepatocyte cell cycle arrest, ductular reaction, activated HSC, and macrophage number after LSG compared with T0. The activation state of HSC was accompanied by modification in the expression of the autophagy marker LC3. Hepatocyte expression of adiponectin was significant higher after LSG than into T0. Moreover, LSG caused decreased resistin expression in Sox9+ hepatic progenitor cells compared with T0. The number of S100A9+ macrophages was also reduced by LSG correlating with resistin expression. Finally, serum levels of proinflammatory cytokines significantly correlated with macrophages and activated HSC numbers. CONCLUSIONS The histologic improvement induced by LSG is associated with the reduced activation of local cellular compartments (hepatic progenitor cells, HSCs, and macrophages), thus, strengthening the role of cellular interactions and hepatic adipocytokine production in the pathogenesis of NAFLD.
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Affiliation(s)
- Valerio Nobili
- Hepatometabolic Unit, Bambino Gesù Children's Hospital, Rome, Italy; Department of Pediatrics and Infantile Neuropsychiatry, Sapienza University of Rome, Italy.
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", Rome, Italy
| | - Francesco De Peppo
- Pediatric Surgery Unit, Bambino Gesù Children's Hospital, Palidoro, Roma, Italy
| | - Romina Caccamo
- Pediatric Surgery Unit, Bambino Gesù Children's Hospital, Palidoro, Roma, Italy
| | - Antonella Mosca
- Hepatometabolic Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Ilaria Romito
- Liver Research Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Anna Alisi
- Liver Research Unit, Bambino Gesù Children's Hospital, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
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33
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Mutgan AC, Besikcioglu HE, Wang S, Friess H, Ceyhan GO, Demir IE. Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer. Mol Cancer 2018; 17:66. [PMID: 29475434 PMCID: PMC5824531 DOI: 10.1186/s12943-018-0806-0] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2017] [Accepted: 02/01/2018] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is unrivalled the deadliest gastrointestinal cancer in the western world. There is substantial evidence implying that insulin and insulin-like growth factor (IGF) signaling axis prompt PDAC into an advanced stage by enhancing tumor growth, metastasis and by driving therapy resistance. Numerous efforts have been made to block Insulin/IGF signaling pathway in cancer therapy. However, therapies that target the IGF1 receptor (IGF-1R) and IGF subtypes (IGF-1 and IGF-2) have been repeatedly unsuccessful. This failure may not only be due to the complexity and homology that is shared by Insulin and IGF receptors, but also due to the complex stroma-cancer interactions in the pancreas. Shedding light on the interactions between the endocrine/exocrine pancreas and the stroma in PDAC is likely to steer us toward the development of novel treatments. In this review, we highlight the stroma-derived IGF signaling and IGF-binding proteins as potential novel therapeutic targets in PDAC.
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Affiliation(s)
- Ayse Ceren Mutgan
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - H Erdinc Besikcioglu
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany.,Department of Histology and Embryology, Gazi University Institute of Health Sciences, Ankara, Turkey
| | - Shenghan Wang
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - Güralp O Ceyhan
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum rechts der Isar, Technical University Munich, München, Germany.
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Abstract
INTRODUCTION The etiology of diabetes is mainly attributed to insulin deficiency due to the lack of β cells (type 1), or to insulin resistance that eventually results in β cell dysfunction (type 2). Therefore, an ultimate cure for diabetes requires the ability to replace the lost insulin-secreting β cells. Strategies for regenerating β cells are under extensive investigation. AREAS COVERED Herein, the authors first summarize the mechanisms underlying embryonic β cell development and spontaneous adult β cell regeneration, which forms the basis for developing β cell regeneration strategies. Then the rationale and progress of each β cell regeneration strategy is reviewed. Current β cell regeneration strategies can be classified into two main categories: in vitro β cell regeneration using pluripotent stem cells and in vivo reprogramming of non-β cells into β cells. Each has its own advantages and disadvantages. EXPERT OPINION Regenerating β cells has shown its potential as a cure for the treatment of insulin-deficient diabetes. Much progress has been made, and β cell regeneration therapy is getting closer to a clinical reality. Nevertheless, more hurdles need to be overcome before any of the strategies suggested can be fully translated from bench to bedside.
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Affiliation(s)
- Shengli Dong
- Department of Biochemistry & Molecular Biology, Louisiana State University Health Science Center, New Orleans, Louisiana
| | - Hongju Wu
- Department of Medicine, Tulane University Health Science Center, New Orleans, Louisiana
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Abstract
OBJECTIVES The side population (SP) contains cells with stem cell/progenitor properties. Previously, we observed that the mouse pancreas SP expanded after pancreatic injury. We aimed to characterize the SP in human pancreas as a potential source of stem cells. METHODS Human organ donor pancreata were fractionated into islets and exocrine tissue, enriched by tissue culture and dispersed into single cells. Cells were phenotyped by flow cytometry, and the SP was defined by efflux of fluorescent dye Hoechst 33342 visualized by ultraviolet excitation. Cells were flow sorted, and their colony-forming potential measured on feeder cells in culture. RESULTS An SP was identified in islet and exocrine cells from human organ donors: 2 with type 1 diabetes, 3 with type 2 diabetes, and 28 without diabetes. Phenotyping revealed that exocrine SP cells had an epithelial origin, were enriched for carbohydrate antigen 19-9 ductal cells expressing stem cell markers CD133 and CD26, and had greater colony-forming potential than non-SP cells. The exocrine SP was increased in a young adult with type 1 diabetes and ongoing islet autoimmunity. CONCLUSIONS The pancreatic exocrine SP is a potential reservoir of adult stem/progenitor cells, consistent with previous evidence that such cells are duct-derived and express CD133.
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Carpino G, Cardinale V, Folseraas T, Overi D, Floreani A, Franchitto A, Onori P, Cazzagon N, Berloco PB, Karlsen TH, Alvaro D, Gaudio E. Hepatic Stem/Progenitor Cell Activation Differs between Primary Sclerosing and Primary Biliary Cholangitis. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 188:627-639. [PMID: 29248458 DOI: 10.1016/j.ajpath.2017.11.010] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/31/2017] [Accepted: 11/16/2017] [Indexed: 02/08/2023]
Abstract
Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are human primary cholangiopathies characterized by the damage of mature cholangiocytes and by the appearance of ductular reaction (DR) as the results of hepatic progenitor cell activation. This study evaluated the differences in progenitor cell niche activation between these two cholangiopathies. Liver tissue was obtained from healthy liver donors (n = 5) and from patients with PSC (n = 20) or PBC (n = 20). DR, progenitor cell phenotype, and signaling pathways were investigated by IHC analysis and immunofluorescence. Our results indicated that DR was more extended, appeared earlier, and had a higher proliferation index in PBC compared with PSC. In PBC, DR was strongly correlated with clinical prognostic scores. A higher percentage of sex determining region Y-box (SOX)9+ and cytokeratin 19+ cells but fewer features of hepatocyte fate characterized progenitor cell activation in PBC versus PSC. Lower levels of laminin and neurogenic locus notch homolog protein 1 but higher expression of wingless-related integration site (WNT) family pathway components characterize progenitor cell niche in PSC compared with PBC. In conclusion, progenitor cell activation differs between PSC and PBC and is characterized by a divergent fate commitment and different signaling pathway predominance. In PBC, DR represents a relevant histologic prognostic marker.
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Affiliation(s)
- Guido Carpino
- Division of Health Sciences, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico," Rome, Italy.
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Trine Folseraas
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Nora Cazzagon
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Pasquale B Berloco
- Department of General Surgery and Organ Transplantation, Sapienza University of Rome, Rome, Italy
| | - Tom H Karlsen
- Norwegian PSC Research Center, Division of Cancer, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway; Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Domenico Alvaro
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
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Activation of Fas/FasL pathway and the role of c-FLIP in primary culture of human cholangiocarcinoma cells. Sci Rep 2017; 7:14419. [PMID: 29089545 PMCID: PMC5663931 DOI: 10.1038/s41598-017-14838-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Accepted: 10/16/2017] [Indexed: 12/13/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) represents a heterogeneous group of malignancies emerging from the biliary tree, often in the context of chronic bile ducts inflammation. The immunological features of iCCA cells and their capability to control the lymphocytes response have not yet been investigated. The aims of the present study were to evaluate the interaction between iCCA cells and human peripheral blood mononuclear cells (PBMCs) and the role of Fas/FasL in modulating T-cells and NK-cells response after direct co-culture. iCCA cells express high levels of Fas and FasL that increase after co-culture with PBMCs inducing apoptosis in CD4+, CD8+ T-cells and in CD56+ NK-cells. In vitro, c-FLIP is expressed in iCCA cells and the co-culture with PBMCs induces an increase of c-FLIP in both iCCA cells and biliary tree stem cells. This c-FLIP increase does not trigger the caspase cascade, thus hindering apoptotis of iCCA cells which, instead, underwent proliferation. The increased expression of Fas, FasL and c-FLIP is confirmed in situ, in human CCA and in primary sclerosing cholangitis. In conclusion our data indicated that iCCA cells have immune-modulatory properties by which they induce apoptosis of T and NK cells, via Fas/FasL pathway, and escape inflammatory response by up-regulating c-FLIP system.
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Culturing and transcriptome profiling of progenitor-like colonies derived from adult mouse pancreas. Stem Cell Res Ther 2017; 8:172. [PMID: 28747214 PMCID: PMC5530554 DOI: 10.1186/s13287-017-0626-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 06/16/2017] [Accepted: 07/03/2017] [Indexed: 12/18/2022] Open
Abstract
Background Transplantation of insulin-producing cells is considered an important diabetes therapy. Many research studies have shown that insulin-producing cells can be derived from the in-vitro cultured pancreatic colonies with self-renewal ability and multilineage potential. Even though these progenitor-like colonies have been prepared from adult pancreas cells, the efficient culture method is hardly established and regulation of the colonies is rarely known. We confirmed previously that single cells acquired from adult mouse pancreas could form cyst-like colonies in a 3D semi-solid system containing Matrigel and methylcellulose. These colonies could be passaged continuously without losing progenitor-like capacity. In the previous culturing system, however, conditioned medium from murine embryonic-stem-cell-derived pancreatic-like cells was used. This unregulated ingredient may reduce repeatability and affect following study. Thus, a new culturing system with certain components needs to be developed. Methods Single cell suspension was acquired from adult mouse pancreas and cultured in a Matrigel-based 3D system with epidermal growth factor, Nicotinamide, B27, and Noggin to form ring colonies. Serial-passage assay was performed to evaluate self-renewal ability. Real-time polymerase chain reaction and immunostaining were used to detect the expression of progenitor-related genes. A 2D differentiation method was used to testify the multilineage potency of the colonies. High-throughput sequencing (HTS) of the colonies was performed to profile the differentially expressed genes. Results We developed a 3D culturing system deprived of conditioned medium to propagate those colonies with high proliferative efficiency. HTS of the transcriptome of mRNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) showed differentially expressed genes compared to the whole pancreas (as control). In mRNAs, several surface marker genes were identified in the colonies. Moreover in noncoding RNAs, miR-21a, miR-31 and miR-155 were upregulated and miR-217, miR-802 and miR-375 were downregulated in colonies along with a number of other miRNAs and lncRNAs. Conclusions Our results offer an efficient culture system for pancreatic progenitor-like colonies and HTS of the colonies serves as a target resource for following study of in-vitro cultured pancreatic progenitors. These findings should also contribute to our understanding of the transcriptional regulation of these progenitor-like colonies and the mechanisms behind their functions. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0626-y) contains supplementary material, which is available to authorized users.
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Moin ASM, Butler PC, Butler AE. Increased Proliferation of the Pancreatic Duct Gland Compartment in Type 1 Diabetes. J Clin Endocrinol Metab 2017; 102:200-209. [PMID: 27813705 PMCID: PMC5413103 DOI: 10.1210/jc.2016-3001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 10/31/2016] [Indexed: 12/13/2022]
Abstract
CONTEXT Pancreatic duct glands (PDGs) have been proposed as a source of regeneration in response to exocrine pancreas injury, and thus may serve as an organ stem cell niche. There is evidence to suggest ongoing β-cell formation in longstanding type 1 diabetes (T1D), but the source is unknown. OBJECTIVE To investigate the PDG compartment of the pancreas in humans with T1D for evidence of an active regenerative signature (presence of progenitor cells and increased proliferation) and, in particular, as a potential source of β-cells. DESIGN, SETTING, AND PARTICIPANTS Pancreases from 46 brain dead organ donors (22 with T1D, 24 nondiabetic controls) were investigated for activation (increased proliferation) and markers of pancreatic exocrine and endocrine progenitors. RESULTS PDG cell replication was increased in T1D (6.3% ± 1.6% vs 0.6% ± 0.1%, P < 0.001, T1D vs nondiabetic), most prominently in association with pancreatic inflammation. There were increased progenitor-like cells in PDGs of T1D, but predominantly with an exocrine fate. CONCLUSION The PDG compartment is activated in T1D consistent with a response to ongoing inflammation, and via resulting ductal hyperplasia may contribute to local obstructive pancreatitis and eventual pancreatic atrophy characteristic of T1D. However, there is no evidence of effective endocrine cell formation from PDGs.
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Affiliation(s)
- Abu Saleh Md Moin
- Larry L. Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California 90095
| | - Peter C Butler
- Larry L. Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California 90095
| | - Alexandra E Butler
- Larry L. Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California 90095
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Lee S, Lee CM, Kim SC. Adult human pancreas-derived cells expressing stage-specific embryonic antigen 4 differentiate into Sox9-expressing and Ngn3-expressing pancreatic ducts in vivo. Stem Cell Res Ther 2016; 7:162. [PMID: 27836003 PMCID: PMC5105312 DOI: 10.1186/s13287-016-0422-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 09/10/2016] [Accepted: 10/14/2016] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Tissue-specific stem/progenitor cells are found in various adult tissues and may have the capacity for lineage-specific differentiation, facilitating applications in autologous transplantation. Stage-specific embryonic antigen 4 (SSEA-4), an early embryonic glycolipid antigen, is expressed in cells derived from adult human pancreas exocrine tissue. Here, we examined the characteristics and lineage-specific differentiation capacity of SSEA-4+ cells. METHODS Human adult partial pancreas tissues were obtained from different donors and cultured in vitro. SSEA-4+ and CA19-9+ cells were isolated from adult human pancreas exocrine cells using magnetic-activated cell sorting, and gene expression was validated by quantitative polymerase chain reaction. To confirm in-vivo differentiation, SSEA-4+ and CA19-9+ cells were transplanted into the dorsal subcutaneous region of mice. Finally, morphological features of differentiated areas were confirmed by immunostaining and morphometric analysis. RESULTS SSEA-4-expressing cells were detected in isolated pancreas exocrine cells from adult humans. These SSEA-4+ cells exhibited coexpression of CA19-9, a marker of pancreatic duct cells, but not amylase expression, as shown by immunostaining and flow cytometry. SSEA-4+ cells exhibited higher relative expression of Oct4, Nanog, Klf4, Sox2, and c-Myc mRNAs than CA19-9+ cells. Pancreatic intralobular ducts (PIDs) were generated from SSEA-4+ or CA19-9+ cells in vivo at 5 weeks after transplantation. However, newly formed PIDs from CA19-9+ cells were less abundant and showed an incomplete PID morphology. In contrast, newly formed PIDs from SSEA-4+ cells were abundant in the transplanted area and showed a crowded morphology, typical of PIDs. Sox9 and Ngn3, key transcription factors associated with pancreatic development and regeneration, were expressed in PIDs from SSEA-4+ cells. CONCLUSIONS SSEA-4-expressing cells in the adult human pancreas may have the potential for regeneration of the pancreas and may be used as a source of stem/progenitor cells for pancreatic cell lineage-specific differentiation.
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Affiliation(s)
- Song Lee
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505 South Korea
| | - Chan Mi Lee
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505 South Korea
| | - Song Cheol Kim
- Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea
- Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505 South Korea
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Corritore E, Lee YS, Sokal EM, Lysy PA. β-cell replacement sources for type 1 diabetes: a focus on pancreatic ductal cells. Ther Adv Endocrinol Metab 2016; 7:182-99. [PMID: 27540464 PMCID: PMC4973405 DOI: 10.1177/2042018816652059] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Thorough research on the capacity of human islet transplantation to cure type 1 diabetes led to the achievement of 3- to 5-year-long insulin independence in nearly half of transplanted patients. Yet, translation of this technique to clinical routine is limited by organ shortage and the need for long-term immunosuppression, restricting its use to adults with unstable disease. The production of new bona fide β cells in vitro was thus investigated and finally achieved with human pluripotent stem cells (PSCs). Besides ethical concerns about the use of human embryos, studies are now evaluating the possibility of circumventing the spontaneous tumor formation associated with transplantation of PSCs. These issues fueled the search for cell candidates for β-cell engineering with safe profiles for clinical translation. In vivo studies revealed the regeneration capacity of the exocrine pancreas after injury that depends at least partially on facultative progenitors in the ductal compartment. These stimulated subpopulations of pancreatic ductal cells (PDCs) underwent β-cell transdifferentiation through reactivation of embryonic signaling pathways. In vitro models for expansion and differentiation of purified PDCs toward insulin-producing cells were described using cocktails of growth factors, extracellular-matrix proteins and transcription factor overexpression. In this review, we will describe the latest findings in pancreatic β-cell mass regeneration due to adult ductal progenitor cells. We will further describe recent advances in human PDC transdifferentiation to insulin-producing cells with potential for clinical translational studies.
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Affiliation(s)
- Elisa Corritore
- Institut de Recherche Expérimentale et Clinique, Pediatric Research Laboratory, Université Catholique de Louvain, Brussels, Belgium
| | - Yong-Syu Lee
- Institut de Recherche Expérimentale et Clinique, Pediatric Research Laboratory, Université Catholique de Louvain, Brussels, Belgium
| | - Etienne M. Sokal
- Institut de Recherche Expérimentale et Clinique, Pediatric Research Laboratory, Université Catholique de Louvain, Brussels, Belgium
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