Stem cell-derived pancreatic islets grown with capillaries induced remission after transplantation in 11 of 13 mice with diabetes, compared with 2 of 14 given islets without blood vessels
Stem cell-derived pancreatic islets grown with capillaries induced remission after transplantation in 11 of 13 mice with diabetes, compared with 2 of 14 given islets without blood vessels
On October 16, Josef Penninger’s group at the University of British Columbia published a method in Cell Stem Cell for growing human stem cell-derived islets with capillaries inside them. Transplanted islets lack oxygen until blood vessels grow into them.
In type 1 diabetes, the immune system kills the insulin-producing β-cells of the pancreas. Researchers are trying to replace these cells by transplanting islets, clusters of hormone-producing cells. Donor islets are in short supply, so researchers grow islets from stem cells. These have already been administered to humans: in Vertex’s 2025 clinical trial, participants received immunosuppressants, and 10 of the 12 who received the full dose no longer needed insulin after a year.
Previous efforts to provide blood vessels for stem cell-derived islets mainly used umbilical vein cells. These cells form large vessels and only partially reproduce the properties of islet blood vessels. Penninger’s group used vascular organoids described in Nature in 2019. These are spherical structures derived from stem cells in which cells that line blood vessels and cells that surround capillaries assemble themselves into a capillary network. After transplantation into mice, they form a vascular tree with blood flowing through it. Penninger founded Angios Biotech, a company developing these organoids.
Islet cells were seeded onto preformed vascular organoids. Within 2–3 days, they formed a combined structure with capillaries inside the islet. After transfer to a gel, the network expanded until its vessel density matched that of donor islets.
The walls of islet capillaries contain small openings called fenestrae, which allow glucose and hormones to pass through rapidly. Vascular organoids alone had very few fenestrae, but these openings appeared in the combined structures. Gene activity analysis predicted that the protein VEGFA was among the signals sent from β-cells to blood vessels: blocking its receptor reduced the number of fenestrae, while a high dose of VEGFA increased their number in vascular organoids alone.
Cells in the vascular organoids protect β-cells. At 1% oxygen, about half of the β-cells in conventional islets died within 18 hours; fewer died in islets with capillaries. Within two days of transplantation into mice, about 25% of the β-cells in conventional islets died; fewer died in islets with capillaries. The protein BMP4 was identified as one mediator of this protection: blocking BMP signaling eliminated the advantage of islets with capillaries, while adding BMP4 protected β-cells in conventional islets.
The researchers induced diabetes with streptozotocin, which kills β-cells, in immunodeficient mice that do not reject human cells. The groups receiving islets were given the same dose under the skin. Subcutaneous transplantation is also feasible in clinical practice, but the blood supply there is poorer than beneath the kidney capsule. Remission was defined as two consecutive fasting glucose measurements at or below 10 mmol/L.
Within two months, remission occurred in 11 of 13 mice given islets with capillaries, 2 of 14 given conventional islets, and 5 of 6 given donor islets. A mixture of islets and vascular organoids combined only at transplantation performed worse than islets grown with capillaries, and its remission rate did not differ from that of conventional islets.
By the eighth week, grafts of islets grown with capillaries contained more human blood vessels than mouse blood vessels. Images showed connections between human and mouse vessels, and a dye injected into the bloodstream reached approximately 40% of the human vessels. The authors suggest that the benefit develops in two stages: vascular cells initially protect β-cells before the mouse’s blood supply reaches the graft, and blood subsequently flows through some of the human vessels.