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Who Will Win: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells for β Cell Replacement and Diabetes Disease Modeling?

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

Purpose of Review

Ever since the reprogramming of human fibroblasts to induced pluripotent stem cells (hiPSCs), scientists have been trying to determine if hiPSCs can give rise to progeny akin to native terminally differentiated cells as human embryonic stem cells (hESCs) do. Many different somatic cell types have been successfully reprogrammed via a variety of methods. In this review, we will discuss recent studies comparing hiPSCs and hESCs and their ability to differentiate to desired cell types as well as explore diabetes disease models.

Recent Findings

Both somatic cell origin and the reprogramming method are important to the epigenetic state of the hiPSCs; however, genetic background contributes the most to differences seen between hiPSCs and hESCs.

Summary

Based on our review of the relevant literature, hiPSCs display differences compared to hESCs, including a higher propensity for specification toward particular cell types based on memory retained from the somatic cell of origin. Moreover, hiPSCs provide a unique opportunity for creating diabetes disease models.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Jin SM, Kim KW. Is islet transplantation a realistic approach to curing diabetes? Korean J Intern Med. 2017;32(1):62–6.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, et al. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282(5391):1145–7.

    Article  CAS  PubMed  Google Scholar 

  3. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72.

    Article  CAS  PubMed  Google Scholar 

  4. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318:1917–20.

    Article  CAS  PubMed  Google Scholar 

  5. Malik N, Rao MS. A review of the methods for human iPSC derivation. Methods Mol Biol. 2013;997:23–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hussein SM, Batada NN, Vuoristo S, Ching RW, Autio R, Narva E, et al. Copy number variation and selection during reprogramming to pluripotency. Nature. 2011;471(7336):58–62.

    Article  CAS  PubMed  Google Scholar 

  7. Nazor KL, Altun G, Lynch C, Tran H, Harness JV, Slavin I, et al. Recurrent variations in DNA methylation in human pluripotent stem cells and their differentiated derivatives. Cell Stem Cell. 2012;10(5):620–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pick M, Stelzer Y, Bar-Nur O, Mayshar Y, Eden A, Benvenisty N. Clone- and gene-specific aberrations of parental imprinting in human induced pluripotent stem cells. Stem Cells. 2009;27(11):2686–90.

    Article  CAS  PubMed  Google Scholar 

  9. Mayshar Y, Ben-David U, Lavon N, Biancotti JC, Yakir B, Clark AT, et al. Identification and classification of chromosomal aberrations in human induced pluripotent stem cells. Cell Stem Cell. 2010;7(4):521–31.

    Article  CAS  PubMed  Google Scholar 

  10. Kim K, Zhao R, Doi A, Ng K, Unternaehrer J, Cahan P, et al. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat Biotechnol. 2011;29(12):1117–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rouhani F, Kumasaka N, de Brito MC, Bradley A, Vallier L, Gaffney D. Genetic background drives transcriptional variation in human induced pluripotent stem cells. PLoS Genet. 2014;10(6):e1004432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ruiz S, Diep D, Gore A, Panopoulos AD, Montserrat N, Plongthongkum N, et al. Identification of a specific reprogramming-associated epigenetic signature in human induced pluripotent stem cells. PNAS. 2012;109(40):16196–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, et al. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. 2011;471(7336):68–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. •• Choi J, Lee S, Mallard W, Clement K, Tagliazucchi GM, Lim H, et al. A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs. Nat Biotechnol. 2015;33(11):1173–81 Study used isogenic hESCs and hiPSCs for comparison to determine the role of genetic background on epigenetic differences between hESCs and hiPSCs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mallon BS, Hamilton RS, Kozhich OA, Johnson KR, Fann YC, Rao MS, et al. Comparison of the molecular profiles of hESCs and hiPSCs of isogenic origin. Stem Cell Res. 2014;12(2):376–86.

    Article  CAS  PubMed  Google Scholar 

  16. Bar-Nur O, Russ HA, Efrat S, Benvenisty N. Epigenetic memory and preferential lineage-specific differentiation in induced pluripotent stem cells derived from human pancreatic islet beta cells. Cell Stem Cell. 2011;9(1):17–23.

    Article  CAS  PubMed  Google Scholar 

  17. •• Thurner M, Shenhav L, Wesolowska-Andersen A, Bennett AJ, Barrett A, Gloyn AL, et al. Genes Associated with Pancreas Development and Function Maintain Open Chromatin in iPSCs Generated from Human Pancreatic Beta Cells. Stem Cell Rep. 2017;9(5):1395–405 The open chromatin structure (associated with active gene transcription) of β cell-derived hiPSCs compared to fibroblast-originating hiPSCs as they relate to open chromatin structures in human islets was studied.

    Article  CAS  Google Scholar 

  18. Drawnel FM, Boccardo S, Prummer M, Delobel F, Graff A, Weber M, et al. Disease modeling and phenotypic drug screening for diabetic cardiomyopathy using human induced pluripotent stem cells. Cell Rep. 2014;9(3):810–21.

    Article  CAS  PubMed  Google Scholar 

  19. Thatava T, Kudva YC, Edukulla R, Squillace K, De Lamo JG, Khan YK, et al. Intrapatient variations in type 1 diabetes-specific iPS cell differentiation into insulin-producing cells. Mol Ther. 2013;21(1):228–39.

    Article  CAS  PubMed  Google Scholar 

  20. •• Braverman-Gross C, Nudel N, Ronen D, Beer NL, McCarty MI, Benvenisty N. Derivation and molecular characterization of pancreatic differentiated MODY1-iPSCs. Stem Cell Res. 2018;31:16–26 hiPSCs were derived from a MODY1 (HNF4A transcription factor mutation) patient and differentiated to the pancreatic lineage. It was reported that the HNF4A target gene's differential expression depends on the number of HNF4A binding sites. The effect is more pronounced if the binding sites are closer to the target gene transcription start site and the target gene has fewer binding sites for other transcription factors in its promoter.

    Article  CAS  PubMed  Google Scholar 

  21. • Teo AK, Lau HH, Valdez IA, Dirice E, Tjora E, Raeder H, et al. Early developmental perturbations in a human stem cell model of MODY5/HNF1B pancreatic hypoplasia. Stem Cell Rep. 2016;6(3):357–67 Human iPSCs were generated from a MODY5 (HFN1B mutation) patient and differentiated to pancreatic cell progenitors. The resulting cells show increased expression of several pancreatic cell transcription factors ( PDX1 , PTF1A , GATA4 , and GATA6 ) and a decrease in PAX6 expression in comparison to the control.

    Article  CAS  Google Scholar 

  22. Stanescu DE, Hughes N, Kaplan B, Stanley CA, De Leon DD. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J Clin Endocrinol Metab. 2012;97(10):E2026–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. • Vethe H, Bjorlykke Y, Ghila LM, Paulo JA, Scholz H, Gygi SP, et al. Probing the missing mature beta-cell proteomic landscape in differentiating patient iPSC-derived cells. Sci Rep. 2017;7(1):4780 Human iPSCs were produced from a MODY1 patient and successfully differentiated into insulin-positive cells. This suggests that a HNF4A mutation does not prevent expression of insulin genes. The differentiated cells were shown to be immature in comparison to human islets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rezania A, Bruin JE, Arora P, Rubin A, Batushansky I, Asadi A, et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat Biotechnol. 2014;32(11):1121–33.

    Article  CAS  PubMed  Google Scholar 

  25. Pagliuca FW, Millman JR, Gurtler M, Segel M, Van Dervort A, Ryu JH, et al. Generation of functional human pancreatic beta cells in vitro. Cell. 2014;159(2):428–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. • Hosokawa Y, Toyoda T, Fukui K, Baden MY, Funato M, Kondo Y, et al. Insulin-producing cells derived from 'induced pluripotent stem cells' of patients with fulminant type 1 diabetes: vulnerability to cytokine insults and increased expression of apoptosis-related genes. J Diabetes Investig. 2017. https://doi.org/10.1111/jdi.12727. Human iPSCs were derived from a patient with fulminant type 1 diabetes to better understand β-cell destruction. Differences were observed vs. control hiPSCs in response to cytokines.

  27. Shang L, Hua H, Foo K, Martinez H, Watanabe K, Zimmer M, et al. β-cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. Diabetes. 2014;63:923–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. La Spada A, Ntai A, Genovese S, Rondinelli M, De Blasio P, Biunno I. Generation of human-induced pluripotent stem cells from Wolfram syndrome type 2 patients bearing the c.103 + 1G>a CISD2 mutation for disease modeling. Stem Cells Dev. 2018;27(4):287–95.

    Article  CAS  PubMed  Google Scholar 

  29. Maehr R, Chen S, Snitow M, Ludwig T, Yagasaki L, Goland R, et al. Generation of pluripotent stem cells from patients with type 1 diabetes. Proc Natl Acad Sci U S A. 2009;106(37):15768–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kudva YC, Ohmine S, Greder LV, Dutton JR, Armstrong A, De Lamo JG, et al. Transgene-free disease-specific induced pluripotent stem cells from patients with type 1 and type 2 diabetes. Stem Cells Transl Med. 2012;1(6):451–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Griscelli F, Ezanno H, Soubeyrand M, Feraud O, Oudrhiri N, Bonnefond A, et al. Generation of an induced pluripotent stem cell (iPSC) line from a patient with maturity-onset diabetes of the young type 3 (MODY3) carrying a hepatocyte nuclear factor 1-alpha (HNF1A) mutation. Stem Cell Res. 2018;29:56–9.

    Article  CAS  PubMed  Google Scholar 

  32. Teo AK, Windmueller R, Johansson BB, Dirice E, Njolstad PR, Tjora E, et al. Derivation of human induced pluripotent stem cells from patients with maturity onset diabetes of the young. J Biol Chem. 2013;288(8):5353–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Siller R, Naumovska E, Mathapati S, Lycke M, Greenhough S, Sullivan GJ. Development of a rapid screen for the endodermal differentiation potential of human pluripotent stem cell lines. Sci Rep. 2016;6:37178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nishizawa M, Chonabayashi K, Nomura M, Tanaka A, Nakamura M, Inagaki A, et al. Epigenetic variation between human induced pluripotent stem cell lines is an indicator of differentiation capacity. Cell Stem Cell. 2016;19(3):341–54.

    Article  CAS  PubMed  Google Scholar 

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Funding

Funding support has been provided by the National Science Foundation (NSF), award CBET-1743367.

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Authors and Affiliations

  1. Department of Chemical and Biological Engineering, Tufts University, Science and Technology Center, Room 276A, Medford, MA, 02155, USA

    Elena F. Jacobson & Emmanuel S. Tzanakakis

  2. Clinical and Translational Science Institute, Tufts Medical Center, Boston, MA, 02111, USA

    Emmanuel S. Tzanakakis

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  1. Elena F. Jacobson
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Correspondence to Emmanuel S. Tzanakakis.

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Elena F. Jacobson and Emmanuel S. Tzanakakis declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Immunology, Transplantation, and Regenerative Medicine

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Jacobson, E.F., Tzanakakis, E.S. Who Will Win: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells for β Cell Replacement and Diabetes Disease Modeling?. Curr Diab Rep 18, 133 (2018). https://doi.org/10.1007/s11892-018-1109-y

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  • DOI: https://doi.org/10.1007/s11892-018-1109-y

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