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Review
. 2020 Jan 23;9(2):283.
doi: 10.3390/cells9020283.

Stem Cell Therapy for Diabetes: Beta Cells versus Pancreatic Progenitors

Bushra Memon  1   2 , Essam M Abdelalim  1   2
Affiliations
Review

Stem Cell Therapy for Diabetes: Beta Cells versus Pancreatic Progenitors

Bushra Memon et al. Cells. .

Abstract

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders. In order to replace the function of the destroyed pancreatic beta cells in diabetes, islet transplantation is the most widely practiced treatment. However, it has several limitations. As an alternative approach, human pluripotent stem cells (hPSCs) can provide an unlimited source of pancreatic cells that have the ability to secrete insulin in response to a high blood glucose level. However, the determination of the appropriate pancreatic lineage candidate for the purpose of cell therapy for the treatment of diabetes is still debated. While hPSC-derived beta cells are perceived as the ultimate candidate, their efficiency needs further improvement in order to obtain a sufficient number of glucose responsive beta cells for transplantation therapy. On the other hand, hPSC-derived pancreatic progenitors can be efficiently generated in vitro and can further mature into glucose responsive beta cells in vivo after transplantation. Herein, we discuss the advantages and predicted challenges associated with the use of each of the two pancreatic lineage products for diabetes cell therapy. Furthermore, we address the co-generation of functionally relevant islet cell subpopulations and structural properties contributing to the glucose responsiveness of beta cells, as well as the available encapsulation technology for these cells.

Keywords: hPSCs; hyperglycemia; insulin-secreting cells; pancreatic islets; transplantation; β-cell precursors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation showing the potential use of human pluripotent stem cell (hPSC) for diabetes treatment. hPSCs derived from the inner cell mass (ICM) of the blastocyst and hiPSCs generated from patient somatic cells can be differentiated into pancreatic progenitors that mature in vivo into glucose-responsive beta cells following transplantation. These pancreatic progenitors can be purified as well as encapsulated prior to transplantation. Alternatively, hPSC-derived pancreatic progenitors can be differentiated into pancreatic beta cells in vitro and then transplanted in diabetic patient. In vitro differentiation to beta cells yields non-committed progenitors or polyhormonal and other endocrine cells. Therefore, these hPSC-derived beta cells can be purified using specific cell surface markers, that could disrupt the islet architecture recapitulated during differentiation, that may result in loss of cellular contact-conferred functional properties.
Figure 2
Figure 2
Different stages of pancreatic beta cell development during the differentiation process. According to Rezania et al. protocol the differentiation of hPSCs into pancreatic beta cells occurs though their differentiation into seven stages, which are confirmed by examining stage-specific markers [8]. Stage 4 (pancreatic progenitors) co-expressing PDX1 and NKX6.1 (PDX1+/NKX6.1+) is currently used in clinical trial for diabetes treatment. PDX1+/NKX6.1+ cells transplanted into mouse model can differentiate in vivo into mature insulin-secreting cells. Furthermore, mature beta cell stage generated in vitro can be directly transplanted into mouse model.
Figure 3
Figure 3
Directed differentiation of human pluripotent stem cells (hPSCs) into pancreatic progenitors and beta cells. Left panel, pancreatic progenitors co-expressing the transcription factors, PDX1 and NKX6.1, are considered bona fide beta cell precursors and can be differentiated with a high efficiency from optimized in vitro protocols [21]. Right panel, hPSC-derived pancreatic beta cells expressing INS alone (monohormonal) (arrows) or INS and GCG (polyhormonal) (arrowheads) (Abdelalim’s lab, unpublished data). PSCs, Pluripotent stem cells; DE, Definitive endoderm; PG, Posterior gut tube; PFG, Posterior foregut; PP, Pancreatic progenitors; EP, Endocrine progenitors; PDX1, Pancreatic and duodenal homeobox 1; NKX6.1, NK6 homeobox 1; INS, INSULIN; GCG, GLUCAGON.
Figure 4
Figure 4
Immuno-modulation strategies for ‘off-the-shelf’ clinical use of human pluripotent stem cell-derived beta cells. A universal product can be developed by combining gene editing for different strategies, such as HLA antigen disruption to reduce immunogenicity and insertion of double suicide switches to eliminate proliferative, non-committed progenitors as well as other pancreatic lineages, thereby enriching insulin-secreting beta cells.
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References

    1. Cnop M., Welsh N., Jonas J.C., Jorns A., Lenzen S., Eizirik D.L. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: Many differences, few similarities. Diabetes. 2005;54(Suppl. 2):S97–S107. doi: 10.2337/diabetes.54.suppl_2.S97. - DOI - PubMed
    1. Murphy R., Ellard S., Hattersley A.T. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat. Clin. Pract. Endocrinol. Metab. 2008;4:200–213. doi: 10.1038/ncpendmet0778. - DOI - PubMed
    1. Vaithilingam V., Tuch B.E. Islet transplantation and encapsulation: An update on recent developments. Rev. Diabet. Stud. 2011;8:51–67. doi: 10.1900/RDS.2011.8.51. - DOI - PMC - PubMed
    1. Latres E., Finan D.A., Greenstein J.L., Kowalski A., Kieffer T.J. Navigating Two Roads to Glucose Normalization in Diabetes: Automated Insulin Delivery Devices and Cell Therapy. Cell Metab. 2019;29:545–563. doi: 10.1016/j.cmet.2019.02.007. - DOI - PubMed
    1. Abdelalim E.M., Bonnefond A., Bennaceur-Griscelli A., Froguel P. Pluripotent stem cells as a potential tool for disease modelling and cell therapy in diabetes. Stem Cell Rev. Rep. 2014;10:327–337. doi: 10.1007/s12015-014-9503-6. - DOI - PubMed

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