TAT-mediated transduction of MafA protein in Utero results in enhanced pancreatic insulin expression and changes in islet morphology

Nancy Vargas, Silvia Álvarez-Cubela, Jaime A. Giraldo, Margarita Nieto, Nicholas M. Fort, Sirlene Cechin, Enrique García, Pedro Espino-Grosso, Christopher Fraker, Camillo Ricordi, Luca A Inverardi, Ricardo Pastori, Juan Dominguez-Bendala

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Alongside Pdx1 and Beta2/NeuroD, the transcription factor MafA has been shown to be instrumental in the maintenance of the beta cell phenotype. Indeed, a combination of MafA, Pdx1 and Ngn3 (an upstream regulator of Beta2/NeuroD) was recently reported to lead to the effective reprogramming of acinar cells into insulin-producing beta cells. These experiments set the stage for the development of new strategies to address the impairment of glycemic control in diabetic patients. However, the clinical applicability of reprogramming in this context is deemed to be poor due to the need to use viral vehicles for the delivery of the above factors. Here we describe a recombinant transducible version of the MafA protein (TAT-MafA) that penetrates across cell membranes with an efficiency of 100% and binds to the insulin promoter in vitro. When injected in utero into living mouse embryos, TAT-MafA significantly up-regulates target genes and induces enhanced insulin production as well as cytoarchitectural changes consistent with faster islet maturation. As the latest addition to our armamentarium of transducible proteins (which already includes Pdx1 and Ngn3), the purification and characterization of a functional TAT-MafA protein opens the door to prospective therapeutic uses that circumvent the use of viral delivery. To our knowledge, this is also the first report on the use of protein transduction in utero.

Original languageEnglish
Article numbere22364
JournalPLoS One
Volume6
Issue number8
DOIs
StatePublished - Aug 10 2011

Fingerprint

insulin
Insulin
Proteins
proteins
acinar cells
glycemic control
Acinar Cells
Therapeutic Uses
Cell membranes
Purification
cell membranes
Transcription Factors
Up-Regulation
Embryonic Structures
transcription factors
Genes
promoter regions
Maintenance
Cell Membrane
cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

TAT-mediated transduction of MafA protein in Utero results in enhanced pancreatic insulin expression and changes in islet morphology. / Vargas, Nancy; Álvarez-Cubela, Silvia; Giraldo, Jaime A.; Nieto, Margarita; Fort, Nicholas M.; Cechin, Sirlene; García, Enrique; Espino-Grosso, Pedro; Fraker, Christopher; Ricordi, Camillo; Inverardi, Luca A; Pastori, Ricardo; Dominguez-Bendala, Juan.

In: PLoS One, Vol. 6, No. 8, e22364, 10.08.2011.

Research output: Contribution to journalArticle

Vargas, Nancy ; Álvarez-Cubela, Silvia ; Giraldo, Jaime A. ; Nieto, Margarita ; Fort, Nicholas M. ; Cechin, Sirlene ; García, Enrique ; Espino-Grosso, Pedro ; Fraker, Christopher ; Ricordi, Camillo ; Inverardi, Luca A ; Pastori, Ricardo ; Dominguez-Bendala, Juan. / TAT-mediated transduction of MafA protein in Utero results in enhanced pancreatic insulin expression and changes in islet morphology. In: PLoS One. 2011 ; Vol. 6, No. 8.
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