title: Lung-Derived Microscaffolds Facilitate Diabetes Reversal after Mouse and Human Intraperitoneal Islet Transplantation.
abstract: There is a need to develop three-dimensional structures that mimic the natural islet tissue microenvironment. Endocrine micro-pancreata (EMPs) made up of acellular organ-derived micro-scaffolds seeded with human islets have been shown to express high levels of key beta-cell specific genes and secrete quantities of insulin per cell similar to freshly isolated human islets in a glucose-regulated manner for more than three months in vitro. The aim of this study was to investigate the capacity of EMPs to restore euglycemia in vivo after transplantation of mouse or human islets in chemically diabetic mice. We proposed that the organ-derived EMPs would restore the extracellular components of the islet microenvironment, generating favorable conditions for islet function and survival. EMPs seeded with 500 mouse islets were implanted intraperitoneally into streptozotocin-induced diabetic mice and reverted diabetes in 67% of mice compared to 13% of controls (p = 0.018, n = 9 per group). Histological analysis of the explanted grafts 60 days post-transplantation stained positive for insulin and exhibited increased vascular density in a collagen-rich background. EMPs were also seeded with human islets and transplanted into the peritoneal cavity of immune-deficient diabetic mice at 250 islet equivalents (IEQ), 500 IEQ and 1000 IEQ. Escalating islet dose increased rates of normoglycemia (50% of the 500 IEQ group and 75% of the 1000 IEQ group, n = 3 per group). Human c-peptide levels were detected 90 days post-transplantation in a dose-response relationship. Herein, we report reversal of diabetes in mice by intraperitoneal transplantation of human islet seeded on EMPs with a human islet dose as low as 500 IEQ.
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Nasser
authors.initials: N
authors.lastname: Abualhassan
authors.affiliation: Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Lena
authors.initials: L
authors.lastname: Sapozhnikov
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Rena L
authors.initials: RL
authors.lastname: Pawlick
authors.affiliation: Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Meygal
authors.initials: M
authors.lastname: Kahana
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pepper
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bruni
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Boris
authors.initials: B
authors.lastname: Gala-Lopez
authors.affiliation: Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kin
authors.affiliation: Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Mitrani
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.|Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada.
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D005109:Extracellular Matrix / Q000737:chemistry*; D006085:Graft Survival; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000098:blood supply; D016381:Islets of Langerhans Transplantation; D008168:Lung / Q000166:cytology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID