Cells, islets, and organoids that evade immune detection and autoimmunity, methods of production and use thereof

An in vitro or ex vivo method of increasing survival or reducing cell death of a transplanted pancreatic islet-like organoid that has been administered to, or transplanted or implanted in, a subject, the method comprising:

• contacting the donor pancreatic islet-like organoid or a pancreatic islet cell, pancreatic β-like islet cell, or pancreatic organoid cell thereof, in vitro or ex vivo, with multiple, intermittent exposures to interferon gamma (IFNγ), said multiple, intermittent in vitro or ex vivo exposures to IFNγ comprising at least 2 or 3 exposures to IFNγ in an amount of about 0.5-100 ng/ml for about 2-12 hours per exposure for a time period of at least about 1- to 3-days;
• wherein the donor pancreatic islet-like organoid or a pancreatic islet cell, pancreatic B-like islet cell, or pancreatic organoid cell thereof is washed and/or rested between the exposures to IFNγ;
• culturing the pancreatic islet-like organoid or a pancreatic islet cell, pancreatic β-like islet cell, pancreatic organoid cell thereof in culture medium comprising about 5-200 ng/ml of Wnt4 or about 25-400 ng/ml of Wnt5a protein for at least about 8 days prior to administration, transplantation, or implantation;
• wherein the multiple intermittent exposures to IFNγ increase survival or reduce cell death of the donor pancreatic islet-like organoid or a pancreatic islet cell, pancreatic β-like islet cell, or pancreatic organoid cell thereof following administration, transplantation, or implantation in the subject;
• and
• wherein the pancreatic islet-like organoid contacted with the multiple, intermittent exposures to IFNγ avoids immune detection;
• exhibits at least one of KCl-stimulated insulin secretion, GLP-1 stimulated insulin secretion, somatostatin secretion, and glucagon secretion;
• and maintains glucose homeostasis in the subject following administration, transplantation, or implantation in the subject.