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 language | English |
|---|---|
| Article number | e22364 |
| Journal | PLoS One |
| Volume | 6 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 10 2011 |
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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 journal › Article
}
TY - JOUR
T1 - TAT-mediated transduction of MafA protein in Utero results in enhanced pancreatic insulin expression and changes in islet morphology
AU - Vargas, Nancy
AU - Álvarez-Cubela, Silvia
AU - Giraldo, Jaime A.
AU - Nieto, Margarita
AU - Fort, Nicholas M.
AU - Cechin, Sirlene
AU - García, Enrique
AU - Espino-Grosso, Pedro
AU - Fraker, Christopher
AU - Ricordi, Camillo
AU - Inverardi, Luca A
AU - Pastori, Ricardo
AU - Dominguez-Bendala, Juan
PY - 2011/8/10
Y1 - 2011/8/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79961159102&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79961159102&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0022364
DO - 10.1371/journal.pone.0022364
M3 - Article
C2 - 21857924
AN - SCOPUS:79961159102
VL - 6
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 8
M1 - e22364
ER -