title: MAFA and T3 Drive Maturation of Both Fetal Human Islets and Insulin-Producing Cells Differentiated From hESC.
abstract: BACKGROUND
  Human embryonic stem cells (hESCs) differentiated toward β-cells and fetal human pancreatic islet cells resemble each other transcriptionally and are characterized by immaturity with a lack of glucose responsiveness, low levels of insulin content, and impaired proinsulin-to-insulin processing. However, their response to stimuli that promote functionality have not been compared.
  
  
  OBJECTIVE
  The objective of the study was to evaluate the effects of our previous strategies for functional maturation developed in rodents in these two human models of β-cell immaturity and compare their responses. Design, Settings, Participants, and Interventions: In proof-of-principle experiments using either adenoviral-mediated overexpression of V-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA) or the physiologically driven path via thyroid hormone (T3) and human fetal islet-like cluster (ICC) functional maturity was evaluated. Then the effects of T3 were evaluated upon the functional maturation of hESCs differentiated toward β-cells.
  
  
  METHODS
  Functional maturation was evaluated by the following parameters: glucose responsiveness, insulin content, expression of the mature β-cell transcription factor MAFA, and proinsulin-to-insulin processing.
  
  
  RESULTS
  ICCs responded positively to MAFA overexpression and T3 treatment as assessed by two different maturation parameters: increased insulin secretion at 16.8 mM glucose and increased proinsulin-to-insulin processing. In hESCs differentiated toward β-cells, T3 enhanced MAFA expression, increased insulin content (probably mediated by the increased MAFA), and increased insulin secretion at 16.8 mM glucose.
  
  
  CONCLUSIONS
  T3 is a useful in vitro stimulus to promote human β-cell maturation as shown in both human fetal ICCs and differentiated hESCs. The degree of maturation induced varied in the two models, possibly due to the different developmental status at the beginning of the study.
authors.affiliation: Joslin Diabetes Center (C.A.-M., J.H.-L., C.Ca., A.S., G.W., S.B.-W.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Chemical Engineering (A.D., C.Co.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307.
authors.forename: Cristina
authors.initials: C
authors.lastname: Aguayo-Mazzucato
authors.affiliation: Joslin Diabetes Center (C.A.-M., J.H.-L., C.Ca., A.S., G.W., S.B.-W.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Chemical Engineering (A.D., C.Co.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307.
authors.forename: Amanda
authors.initials: A
authors.lastname: DiIenno
authors.affiliation: Joslin Diabetes Center (C.A.-M., J.H.-L., C.Ca., A.S., G.W., S.B.-W.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Chemical Engineering (A.D., C.Co.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.affiliation: Joslin Diabetes Center (C.A.-M., J.H.-L., C.Ca., A.S., G.W., S.B.-W.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Chemical Engineering (A.D., C.Co.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cahill
authors.affiliation: Joslin Diabetes Center (C.A.-M., J.H.-L., C.Ca., A.S., G.W., S.B.-W.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Chemical Engineering (A.D., C.Co.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307.
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Joslin Diabetes Center (C.A.-M., J.H.-L., C.Ca., A.S., G.W., S.B.-W.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Chemical Engineering (A.D., C.Co.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307.
authors.forename: Gordon
authors.initials: G
authors.lastname: Weir
authors.affiliation: Joslin Diabetes Center (C.A.-M., J.H.-L., C.Ca., A.S., G.W., S.B.-W.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Chemical Engineering (A.D., C.Co.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307.
authors.forename: Clark
authors.initials: C
authors.lastname: Colton
authors.affiliation: Joslin Diabetes Center (C.A.-M., J.H.-L., C.Ca., A.S., G.W., S.B.-W.), Harvard Medical School, Boston, Massachusetts 02215; and Department of Chemical Engineering (A.D., C.Co.), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307.
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism*; D014284:Triiodothyronine / Q000494:pharmacology*
chemical_list: D007328:Insulin; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large; D014284:Triiodothyronine; D005947:Glucose