Details

Autor(en) / Beteiligte

• Forbes, Shareen
• Bond, Andrew R
• Thirlwell, Kayleigh L
• Burgoyne, Paul
• Samuel, Kay
• Noble, June
• Borthwick, Gary
• Colligan, David
• McGowan, Neil W A
• Lewis, Philip Starkey
• Fraser, Alasdair R
• Mountford, Joanne C
• Carter, Roderick N
• Morton, Nicholas M
• Turner, Marc L
• Graham, Gerard J
• Campbell, John D M

Titel

Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization

Ist Teil von

• Science translational medicine, 2020-01, Vol.12 (526)

Ort / Verlag

United States

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.