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Emerging routes to the generation of functional β-cells for diabetes mellitus cell therapy


Diabetes mellitus, which affects more than 463 million people globally, is caused by the autoimmune ablation or functional loss of insulin-producing β-cells, and prevalence is projected to continue rising over the next decades. Generating β-cells to mitigate the aberrant glucose homeostasis manifested in the disease has remained elusive. Substantial advances have been made in producing mature β-cells from human pluripotent stem cells that respond appropriately to dynamic changes in glucose concentrations in vitro and rapidly function in vivo following transplantation in mice. Other potential avenues to produce functional β-cells include: transdifferentiation of closely related cell types (for example, other pancreatic islet cells such as α-cells, or other cells derived from endoderm); the engineering of non-β-cells that are capable of modulating blood sugar; and the construction of synthetic ‘cells’ or particles mimicking functional aspects of β-cells. This Review focuses on the current status of generating β-cells via these diverse routes, highlighting the unique advantages and challenges of each approach. Given the remarkable progress in this field, scalable bioengineering processes are also discussed for the realization of the therapeutic potential of derived β-cells.

Key points

  • Recent advances in human stem cell differentiation protocols enable the generation of mature β-cells with dynamic insulin secretion and metabolic properties akin to primary human β-cells.

  • In addition to β-cells, other hormone-expressing islet cell types are generated under current differentiation protocols.

  • The unlimited source provided by stem cell-derived β-cells and islet clusters would address the current scarcity in cadaveric donor tissues for islet transplantation, and sophisticated gene-editing tools could be used to cloak them against immune attack.

  • Transdifferentiation of endogenous non-β-cells to insulin-producing cells could be exploited as an alternative strategy to increase the number of functional β-cell equivalents.

  • Bioreactors are emerging as technologies for enabling diabetes mellitus cell therapies; these platforms allow precise control of critical cultivation factors for optimized large-scale stem cell differentiation towards functional islet cells.

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Fig. 1: Advances in the generation of mature β-cells from hPSCs and their application for diabetes mellitus cell therapy.
Fig. 2: Transdifferentiation of closely related endoderm-derived somatic cells to β-like cells.
Fig. 3: Stem cell bioprocessing for pancreatic islet cell manufacturing.


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The authors thank S. Puri and N. Kerper of the M. Hebrok laboratory and E. Jacobson of the E. Tzanakakis laboratory for insightful comments during the preparation of the manuscript. G.G.N. was supported by a JDRF postdoctoral fellowship (3-PDF-2016-195-A-N). Research in the M. Hebrok laboratory is supported by grants from the NSF (NSF CBET-1743407) and NIH (R01DK105831). Research in the E. Tzanakakis laboratory is supported by grants from the NSF (NSF CBET-1743367; CBET-1951104). The figures were originally prepared with the help of Biorender and Adobe Illustrator.

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G.G.N. and E.S.T. researched data for the article. All authors made substantial contributions to the discussion of the content, wrote the article and carried out review/editing of the manuscript before submission.

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Correspondence to Matthias Hebrok.

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Competing Interests

M.H. is affiliated with Semma Therapeutics (Consultant and SAB member) and Encellin Inc. (SAB member, stock holder). M.H. also holds stocks from Viacyte Inc.. The other authors declare no competing interests.

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Nature Reviews Endocrinology thanks H. Lickert, A. Stewart and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Artificial pancreas

A mechanical device devoid of cells that integrates glucose sensors with insulin pumps to dispense insulin as needed with minimal input from the patient.

Macroencapsulation devices

Sealed devices constructed out of a selectively permeable membrane that are filled with cells either free floating or in a matrix, wherein the cells can still exert their therapeutic effect.

TGFβ-induced factor homeobox 2

A transcription factor whose expression separates the pancreatic from the liver lineage early in embryonic development.

Stirred suspension bioreactors

Vessels for cultivation of cells that feature an impeller for mixing, probes for monitoring the culture environment, ports for sampling and exchange of medium, and assemblies for aeration and maintenance of temperature.

Agitation-induced shear

Shear in the liquid phase of bioreactor cultures arising from spatial gradients of velocity due to stirring.

Chimeric antigen receptors

(CARs). Novel receptors designed to bind to specific proteins on cells (for example, cancer cells). T cells are engineered with CARs to provide new targeting ability.

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Nair, G.G., Tzanakakis, E.S. & Hebrok, M. Emerging routes to the generation of functional β-cells for diabetes mellitus cell therapy. Nat Rev Endocrinol 16, 506–518 (2020).

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