In:
PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 8 ( 2023-8-24), p. e0290460-
Abstract:
Novel biotherapies for Type 1 Diabetes that provide a significantly expanded donor pool and that deliver all islet hormones without requiring anti-rejection drugs are urgently needed. Scoring systems have improved islet allotransplantation outcomes, but their use may potentially result in the waste of valuable cells for novel therapies. To address these issues, we created “Neo-Islets” (NIs), islet-sized organoids, by co-culturing in ultralow adhesion flasks culture-expanded islet (ICs) and Mesenchymal Stromal Cells (MSCs) (x 24 hrs, 1:1 ratio). The MSCs exert powerful immune- and cyto-protective, anti-inflammatory, proangiogenic, and other beneficial actions in NIs. The robust in vitro expansion of all islet hormone-producing cells is coupled to their expected progressive de-differentiation mediated by serum-induced cell cycle entry and Epithelial-Mesenchymal Transition (EMT). Re-differentiation in vivo of the ICs and resumption of their physiological functions occurs by reversal of EMT and serum withdrawal-induced exit from the cell cycle. Accordingly, we reported that allogeneic, i.p.-administered NIs engraft in the omentum, increase Treg numbers and reestablish permanent normoglycemia in autoimmune diabetic NOD mice without immunosuppression. Our FDA-guided pilot study (INAD 012–0776) in insulin-dependent pet dogs showed similar responses, and both human- and canine-NIs established normoglycemia in STZ-diabetic NOD/SCID mice even though the utilized islets would be scored as unsuitable for transplantation. The present study further demonstrates that islet gene expression profiles (α, β, γ, δ) in human “non-clinical grade” islets obtained from diverse, non-diabetic human and canine donors (n = 6 each) closely correlate with population doublings, and the in vivo re-differentiation of endocrine islet cells clearly corresponds with the reestablishment of euglycemia in diabetic mice. Conclusion: human-NIs created from diverse, “non-clinical grade” donors have the potential to greatly expand patient access to this curative therapy of T1DM, facilitated by the efficient in vitro expansion of ICs that can produce ~ 270 therapeutic NI doses per donor for 70 kg recipients.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0290460
DOI:
10.1371/journal.pone.0290460.g001
DOI:
10.1371/journal.pone.0290460.g002
DOI:
10.1371/journal.pone.0290460.g003
DOI:
10.1371/journal.pone.0290460.g004
DOI:
10.1371/journal.pone.0290460.t001
DOI:
10.1371/journal.pone.0290460.t002
DOI:
10.1371/journal.pone.0290460.t003
DOI:
10.1371/journal.pone.0290460.t004
DOI:
10.1371/journal.pone.0290460.s001
DOI:
10.1371/journal.pone.0290460.s002
DOI:
10.1371/journal.pone.0290460.s003
DOI:
10.1371/journal.pone.0290460.s004
DOI:
10.1371/journal.pone.0290460.s005
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2267670-3
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