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Organoids control glucose

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Science Translational Medicine  02 Sep 2020:
Vol. 12, Issue 559, eabe4433
DOI: 10.1126/scitranslmed.abe4433

Abstract

Human islet-like organoids improve glucose control in immunocompetent mice.

Stem cell therapies represent an exciting avenue to regenerate cells or organs in the body; however, their clinical utility is currently limited to hemopoietic stem cell transplantation. To overcome limitations of therapeutic stem cell technologies, several ongoing research efforts focus on implanting stem cell–derived mature cells or three-dimensional collection of cells (so-called “organoids”) into the body, with the hope of restoring function after the original cells have degenerated.

Yoshihara and co-workers generated insulin-producing pancreatic islet–like organoids from induced pluripotent stem cells (iPSCs), with the goal of treating diabetes. As a critical player in cell maturation, they identified WNT4 signaling, which allowed direct derivation of human islet–like organoids (HILOs) from iPSCs without requiring additional cells. HILOs resembled human pancreatic islets and produced insulin upon glucose stimulation. Transplantation of HILOs into the kidney capsule of diabetic mice allowed animals to regain glycemic control.

Immune responses are, however, critical factors limiting the therapeutic efficiency of cell or organoid transplantation, particularly in type 1 diabetes, which is primarily an immune-mediated disease. To investigate how immune responses can be avoided, the authors applied interferon γ (IFN-γ), a cytokine that increases the expression of the immunosuppressant programmed death–ligand 1 (PD-L1) on the surface of the organoids. Continuous in vivo treatment of patients with IFN-γ, however, would significantly limit translation of this technology to the clinic, as cytokines can induce β cell death and dedifferentiation of organoid cells. As an alternative solution, the team worked out a protocol using multiple short exposures of organoids to IFN-γ before implantation. This method was sufficient to induce epigenetic memory and long-lasting PD-L1 expression after the cytokine treatment was ceased. Most importantly, PD-L1-expressing, immune-evasive organoids were able to maintain glucose control in immunocompetent mice up to 50 days after transplantation.

The derivation of allogenic, immune-evasive islet-like organoids using a chemically defined standardized protocol has obvious translation potential. Several technical challenges have yet to be solved, including quality control of organoids and scale-up of the technology. A further limitation is whether these organoids can retain functionality in vivo long-term. Chronic rejection and atrophy of the organoids are potential long-term concerns that have to be addressed before planning the first-in-human clinical trial. Nevertheless, glycemic control using miniature living glucose controllers in immunocompetent organisms could potentially revolutionize diabetes treatment.

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