Abstract
Islet transplantation effectively treats diabetes but relies on immune suppression and is practically limited by the number of cadaveric islets available. An alternative cellular source is insulin-producing cells derived from pluripotent cell sources. Three animal cohorts were used in the current study to evaluate whether an oxygen-providing macro-encapsulation device, 'βAIR', could function in conjunction with human embryonic stem cells (hESCs) and their derivatives. The first cohort received macro-encapsulated undifferentiated hESCs, a second cohort received hESCs differentiated to a pancreatic progenitor state with limited endocrine differentiation. A reference cohort received human islets. Macro-encapsulation devices were implanted subcutaneously and monitored for up to 4 months. Undifferentiated pluripotent stem cells did not form teratoma but underwent cell death following implantation. Human C-peptide (hC- peptide) was detectable in host serum one week after implantation for both other cohorts. hC-peptide levels decreasing over time but remained detectable up to the end of the study. Key factors associated with mature endocrine cells were observed in grafts recovered from cohorts containing islets and hESC-derivatives including C-peptide, insulin, glucagon and urocortin 3. We conclude that the 'βAIR' macroencapsulation device is compatible with both human islets and pluripotent derivatives, but has a limited capability of sustaining undifferentiated pluripotent cells.
Highlights
Islet transplantation is an effective treatment for type I diabetes (1,2 and http:// www.citregistry.org/)
Considerable advancements in differentiating pluripotent cultures into functional pancreatic endocrine cells have occurred over the last decade [5,6,7,8,9,10], and normoglycemic restoration in diabetic mice through the implantation of such cells has been demonstrated [6,8,9,11,12] The best-known approach, pioneered by Kroon et al 6, relies on implantation of pancreatic progenitors in a protective sac which in turn differentiate in vivo to form mature functional endocrine cells by an as yet poorly understood mechanism [8,13,14] The in vivo maturation process generally takes [2,3] months, and preclinical testing demands the use of immunocompromised animals
We demonstrate that macroencapsulation within the ‘βAIR’ device can successfully sustain human islets and human embryonic stem cells (hESCs) derivatives within a non-immunosuppressed host
Summary
Islet transplantation is an effective treatment for type I diabetes (1,2 and http:// www.citregistry.org/). Patient demand for islets of Langerhans far exceeds the numbers available for transplantation, severely limiting this treatment option. HESCs have an unlimited growth potential and the capacity to differentiate to any cell-type of the body 3. Combined, these qualities imply the possibility of a limitless source of insulin producing beta-cells. Evaluation of encapsulation technologies have been performed using human islets (reviewed in 15)
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