Molecular Cell and Developmental Biology : Faculty Detail

Juan Dominguez-Bendala, Ph.D.

Research Associate Professor of Diabetes Research Institute/Surgery and Cell Biology

305-243-4092 (office)

DRI room 5008

jdominguez2@med.miami.edu

Curriculum Vitae

B.S., 1993, Universidad de Sevilla, Sevilla, Spain
M.S., 1997, University College London (University of London), UK
Ph.D., 2000, Roslin Institute/Edinburgh, UK
Postdoctoral Associate, 2001-2004, University of Miami Miller School of Medicine
Research Assistant Professor, 2005-2001, University of Miami Miller School of Medicine
Research Associate Professor, 2010-present, University of Miami Miller School of Medicine
Director of Stem Cell Development for Translational Research at the Diabetes Research Institute, 2010-present

Research Interests

Our research is focused on the differentiation of stem cells into insulin-producing beta cells for transplantation in type 1 diabetic patients. We work both on human adult and embryonic stem cells. From a translational point of view, our research program requires not only the development of efficient in vitro differentiation protocols but also the implementation of measures to make the transplantation of the cells safe in a clinical context.

Our efforts at differentiating hES cells into beta cells are based on an array of novel technologies that we have largely pioneered in this field. When most competing teams pursue strategies based on the sequential addition of soluble factors, we have established key collaborations with molecular biologists and bioengineers to develop alternative approaches based on: (a) protein transduction, a technique designed to bypass extracellular signals; (b) the identification and use of oxygen as a key regulator of beta cell specification; and (c) the identification and use of critical microRNAs involved in islet biogenesis. In addition to relevant research publications on each of these themes, our recent review “Oxygen: a master regulator of pancreatic development?” [Biol. Cell 101 (8):431-440] proposes a new model that, if validated, might represent a paradigm shift in our understanding of organogenesis.

Beyond its well-known role as an electron acceptor in aerobic respiration, oxygen is also
a key effector of many developmental events. The oxygen-sensing machinery and the very
fabric of cell identity and function have been shown to be deeply intertwined. Here we take
a first look at how oxygen might lie at the crossroads of the major molecular pathways that
shape the development of the pancreas. Based on a thorough review of the literature, we
present a theoretical model whereby evolving oxygen tensions during development might
choreograph to a large extent the sequence of molecular events resulting in the formation
of the endocrine and exocrine compartments of the pancreas.

Fraker et al [Biol. Cell 101 (8):431-440]

As for the safety aspect of our research, we designed a double fail-safe, suicide gene-based mechanism that, upon completion of ES cell differentiation protocols, would result in the selective elimination of (a) non-beta cells and (b) proliferating cells. This proposal was originally funded by the Juvenile Diabetes Research Foundation.

We are also engaged in active research on transdifferentiation (also termed reprogramming), which is the direct conversion of one tissue type into another. In particular, we are looking at the acinar compartment of the pancreas as a potentially plentiful supply of cells with the ability to be redirected to the beta cell phenotype. Protein transduction is our technology of choice to accomplish this goal.

More recently, we have also turned our attention to the generation of induced pluripotent stem (iPS) cells as a potential tool to tailor ES-like cells to individual patients. The proposed approach, also based on protein transduction, would remove the main obstacle (namely, the use of viral vehicles for reprogramming) that prevents the clinical use of iPS cells. This project was recently funded by the NIH.

All the above projects are the result of an active research of potential synergies with other groups with complementary expertise. Another example is our recently awarded NIH SBIR project “a novel perfluorocarbon-based culture device for islet cell biology applications”, in which we partnered with a bioengineering company to devise new culture methods for beta cell applications based on our patent-pending oxygen-delivery platforms.

Recent Publications

Rosero, S., Bravo-Egana, V., Jiang, Z., Khuri, S., Tsinoremas, N., Klein, D., Sabates, E., Correa-Medina, M., Ricordi, C., Domínguez-Bendala, J., Diez, J., and Pastori, R.L. MicroRNA signature of the human developing pancreas. BMC Genomics 2010; 11:509.

Hmadcha, A., Domínguez-Bendala, J., Arredounai, M., Soria, B. The immune boundaries for stem cell based therapies: problems and prospective solutions. Journal of Cellular and Molecular Medicine, J Cell Mol Med. 2009 Aug;13(8A):1464-75.

C.-Y. Charles Huang, Daniel Peláez, Juan Domínguez Bendala, Franklin Garcia-Godoy, Herman S. Cheung. Pluripotency of Stem Cells Derived From Adult Periodontal Ligament. Regen. Med. 2009 Nov; 4(6):809-21.

Fraker, C., Ricordi, R., Inverardi, L., Domínguez-Bendala. Oxygen: a master regulator of pancreatic development? Biology of the Cell, 2009. 101 (8): 431-440.

Szeto, A., Nation, DA., Mendez, AJ., Domínguez-Bendala, J., Brooks, LG., Schneiderman, N., McCabe, PM. Oxytocin attenuates NADPH-dependent superoxide activity and IL-6 secretion in macrophages and vascular cells. American Journal of Physiology, Endocrinology and Metabolism, 2008. 295(6):1495-501.

Martin-Pagola A., Sisino G., Allende G., Domínguez-Bendala J., Gianani R., Reijonen H., Nepom G.T., Ricordi C., Ruiz P., Sageshima J., Ciancio G., Burke1 G.W., Pugliese, A. Insulin Expression and Proliferation in Ductal Cells in the Transplanted Pancreas of Patients with Type 1 Diabetes and Recurrence of Autoimmunity. Diabetologia, 2008. 51(10): 1083-13.

Bravo-Egana V., Rosero S., Molano R.D., Pileggi A., Ricordi C., Dominguez-Bendala J., Pastori, R.L. Quantitative differential expression analysis reveals miR-7 as major islet microRNA. Biochem Biophys Res Commun. 2008 Feb 22; 366(4):922-6.

Fraker, C., Álvarez, S., Papadopoulos, P., Giraldo, J., Gu, W., Inverardi, L., Ricordi, C. and Domínguez-Bendala, J. Enhanced oxygenation promotes beta cell differentiation in vitro. Stem Cells. 2007 Dec; 25(12):3155-64

Goicoa, S., Álvarez, S., Ricordi, C., Inverardi, L. and Domínguez-Bendala, J. Sodium butyrate induces genes of early pancreatic differentiation in ES cells. Cloning and Stem Cells 8(3):140-149 (2006).

J. Domínguez-Bendala, C. Ricordi and R. Pastori. Protein transduction: a novel approach to induce in vitro pancreatic differentiation. Cell Transplantation, 2006; 15 Suppl. 1:85-90.

Domínguez-Bendala J, Masutani M, McWhir J. Down-regulation of PARP-1, but not of Ku80 or DNA-PKcs', results in higher gene targeting efficiency. Cell Biol Int. 2006 Apr; 30(4):389-93.

Domínguez-Bendala, J. and Ricordi, C. Stem cell plasticity and tissue replacement. Cell Transplantation 14(7): 423-425, 2005

Domínguez-Bendala J., Klein D., Ribeiro M., Ricordi C., Inverardi L., Pastori R. and Edlund H. TAT-mediated ngn3 protein transduction stimulates pancreatic endocrine differentiation in vitro. Diabetes 54:720-726, 2005

Domínguez-Bendala, J. and McWhir, J. Enhanced gene targeting frequency in ES cells with low genomic methylation levels. Transgenic Research 13(1):69-74, 2004

Domínguez-BendalaJ, Priddle H, ClarkeA & McWhir, J. Elevated expression of exogenous Rad51 leads to identical increases in gene targeting frequency in murine embryonic stem (ES) cells with both functional and dysfunctional p53 genes. Experimental Cell Research 10;286(2):298-307, 2003

Domínguez-Bendala, J and Ricordi, C. Stem cells in Reparative Medicine. Cell Transplantation 12(4):329-34, 2003

Domínguez-Bendala J, Inverardi L., Ricordi, C. Stem cells and their clinical application. Transplantation Proceedings, 34: 1372-1375, 2002

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