Alginate-microencapsulation of human stem cell-derived ß cells with CXCL12 prolongs their survival and function in immunocompetent mice without systemic immunosuppression.
Am J Transplant
; 19(7): 1930-1940, 2019 07.
Article
in En
| MEDLINE
| ID: mdl-30748094
ABSTRACT
Pancreatic ß-cell replacement by islet transplantation for the treatment of type 1 diabetes (T1D) is currently limited by donor tissue scarcity and the requirement for lifelong immunosuppression. The advent of in vitro differentiation protocols for generating functional ß-like cells from human pluripotent stem cells, also referred to as SC-ß cells, could eliminate these obstacles. To avoid the need for immunosuppression, alginate-microencapsulation is widely investigated as a safe path to ß-cell replacement. Nonetheless, inflammatory foreign body responses leading to pericapsular fibrotic overgrowth often causes microencapsulated islet-cell death and graft failure. Here we used a novel approach to evade the pericapsular fibrotic response to alginate-microencapsulated SC-ß cells; an immunomodulatory chemokine, CXCL12, was incorporated into clinical grade sodium alginate to microencapsulate SC-ß cells. CXCL12 enhanced glucose-stimulated insulin secretion activity of SC-ß cells and induced expression of genes associated with ß-cell function in vitro. SC-ß cells co-encapsulated with CXCL12 showed enhanced insulin secretion in diabetic mice and accelerated the normalization of hyperglycemia. Additionally, SC-ß cells co-encapsulated with CXCL12 evaded the pericapsular fibrotic response, resulting in long-term functional competence and glycemic correction (>150 days) without systemic immunosuppression in immunocompetent C57BL/6 mice. These findings lay the groundwork for further preclinical translation of this approach into large animal models of T1D.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stem Cells
/
Islets of Langerhans Transplantation
/
Diabetes Mellitus, Experimental
/
Diabetes Mellitus, Type 1
/
Alginates
/
Insulin-Secreting Cells
/
Chemokine CXCL12
/
Graft Survival
Type of study:
Guideline
/
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
Am J Transplant
Journal subject:
TRANSPLANTE
Year:
2019
Document type:
Article