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Liver to Pancreas Transdifferentiation

  • Immunology, Transplantation, and Regenerative Medicine (L Piemonti and V Sordi, Section Editors)
  • Published:
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Abstract

Purpose of the Review

Here, we review recent findings in the field of generating insulin-producing cells by pancreatic transcription factor (pTF)-induced liver transdifferentiation (TD). TD is the direct conversion of functional cell types from one lineage to another without passing through an intermediate stage of pluripotency. We address potential reasons for the restricted efficiency of TD and suggest modalities to overcome these challenges, to bring TD closer to its clinical implementation in autologous cell replacement therapy for insulin-dependent diabetes.

Recent Findings

Liver to pancreas TD is restricted to cells that are a priori predisposed to undergo the developmental process. In vivo, the predisposition of liver cells is affected by liver zonation and hepatic regeneration. The TD propensity of liver cells is related to permissive epigenome which could be extended to TD-resistant cells by specific soluble factors. An obligatory role for active Wnt signaling in continuously maintaining a “permissive” epigenome is suggested. Moreover, the restoration of the pancreatic niche and vasculature promotes the maturation of TD cells along the β cell function.

Summary

Future studies on liver to pancreas TD should include the maturation of TD cells by 3D culture, the restoration of vasculature and the pancreatic niche, and the extension of TD propensity to TD-resistant cells by epigenetic modifications. Liver to pancreas TD is expected to result in the generation of custom-made “self” surrogate β cells for curing diabetes.

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Acknowledgments

We thank the present and former students and post-doctorate fellows for their enormous contribution during the years.

Funding

Funding supporting part of the presented studies include JDRF, ISF, D-Cure, BioDisc and EFSD, “Autologous cell replacement therapy for diabetic patients by liver cells transdifferentiation” (Dia-cure), P_37_794, POC-A. 1- A.1.1.4-E-2015 (2016 - 2020)/ SMIS 106897, Orgenesis Ltd.

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Authors and Affiliations

  1. The Sheba Regenerative Medicine, Stem Cell and Tissue Engineering Center, Sheba Medical Center, 56261, Tel-Hashomer, Israel

    Irit Meivar-Levy & Sarah Ferber

  2. Dia-Cure, Institute of Medical Scientific Research Acad. Nicolae Cajal, University Titu Maiorescu, Bucharest, Romania

    Irit Meivar-Levy & Sarah Ferber

  3. Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel

    Sarah Ferber

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  1. Irit Meivar-Levy
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Correspondence to Sarah Ferber.

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Conflict of Interest

Irit Meivar-Levy is a Senior Scientist at Orgenesis LTD. In addition, Dr. Meivar-Levy has a patent which is licensed to Orgenesis.

Sarah Ferber is the CSO of Orgenesis Inc. In addition, Dr. Ferber has several patents on Transdifferentiation, which are licensed to Orgenesis.

Human and Animal Rights and Informed Consent

Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of Sheba Medical Center Committee on Clinical Investigations (the institutional review board; 0395-13-SMC) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted and ethical approval was obtained from the Institutional Animal Care and Use Committee of Sheba Medical Center (1023/16, 732/12).

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Meivar-Levy, I., Ferber, S. Liver to Pancreas Transdifferentiation. Curr Diab Rep 19, 76 (2019). https://doi.org/10.1007/s11892-019-1198-2

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