I am a physician-scientist with a broad background in transfusion medicine, cell therapies, hematology and stem cell biology. My long-standing interest in hematopoiesis began during my doctoral and postdoctoral work in the Cancer Research Institute of Barcelona, the Erasmus University of Rotterdam and Cincinnati Children’s. This work and my work as an independent investigator thereafter developed methods and proof-of-concept for analysis of signaling pathways in blood and bone marrow cells. This work has been developed in the Division of Experimental Hematology and Cancer Biology of the Cancer & Blood Diseases Institute of Cincinnati Children’s, where I am Professor of Pediatrics and Stem Cell Program leader.
I am the Director of the Hoxworth Blood Center, a center with a national and international reputation for its interest in developing and validating new blood products for transfusion and transplantation. Hoxworth Blood Center is the only community blood center owned and operated by a University in the United States and is the blood provider to all 30 hospitals of the Greater Cincinnati and cell therapy products to four stem cell transplantation programs in Cincinnati and Akron, Ohio. I am also the Director of the Translational Core Laboratories at Cincinnati Children’s and the medical director for Cell Therapies at Hoxworth Blood Center.
My long-term goal is the development of new blood and cell therapy products with augmented efficacy and/or safety profiles in the areas of cell/gene therapies as well as identifying and targeting novel targets for intervention in pediatric B-acute lymphoblastic leukemia. My lab aims to improve current protocols of cell-based and small-molecule development for treatment of hematological malignancies.
Specifically, my basic biology laboratory has been pivotal in the elucidation of the cellular and molecular mechanisms of hematopoietic cell activity through the Rho family of GTPases in health and disease. We provided the basis for understanding of the physiological cell-autonomous and microenvironment/cytokine dependent mechanisms in the context of myeloid progenitor migration and bone marrow retention. Our group is now actively searching for the mechanisms that control cold platelet damage and identified key molecular signals and methods to prevent cold storage damage. Our group also defined the mechanisms that control oncogenic tyrosine kinase signals dependent transformation in leukemic progenitors and identifying specific intrinsic and microenvironment-dependent signaling through Rho GTPases.
In the last 10 years, my group has focused on the most frequent of the pediatric cancers, acute B-cell lymphoblastic leukemia. While the curation rates of this tumor have significantly improved in the last 40 years to reach ~90%, the remaining high toxicity of the existing therapies and the fact that the children who do not get cured represent a population as a large as pediatric AML or pediatric glioblastomas, compelled me towards working towards understanding and identifying targets for intervention in B-ALL. Our group identified the role of aPKC/Satb2 and Vav3 as novel genes controlling the epigenetic silencing of hotspot genes required for proliferation and differentiation arrest of B-cell progenitors/precursors.
Through hematopoietic differentiation of human induced pluripotent stem cells (iPSC) from SCN patients, our laboratory has unveiled the pathogenetic mechanisms of neutropenia in patients with ELANE mutations resulting in neutrophil elastase intracellular mislocalization, endoplasmic reticulum stress and apoptosis along with a non-cell autonomous effect on myeloid progenitors responsible to a bias towards monocytosis. Our laboratory has also developed specific methods for the characterization of iPSC from the progenitor cell biology consortium and developed/validated new methods for cryopreservation/delivery of functionally active lymphocyte populations in the context of adoptive transplantation.
My pre-clinical/clinical group in Transfusion Medicine has optimized methods of progenitor and granulocyte collection for transfusion in neutropenic patients and validated novel methods to preserve and store red cells, platelets and T cells in clinical multi-center trials.
As a clinician, I am a licensed physician in the states of Ohio and Kansas (inactive) and am active as a physician in Transfusion Medicine. As medical director for Cell Therapies, I serve in five different stem cell transplantation programs. I am also the Director and Medical Director of the Translational Core Laboratories, supervising the production of multiple gene therapy and CAR-T cell therapy production as well as a very busy vector production facility (for gamma-retroviral and lentiviral vector production). I have abundant experience in the regulatory aspects of biological product licensing and I (and my group) have supported multiple clinical trials and trial designs and discussions with the US FDA CBER and acted as a consultant for multiple trials before the FDA CBER.
As a researcher, my research is funded through the National Institutes of Health (PI or co-PI of 4 NIH R01 or equivalent grants), Department of Defense, private foundations and different corporations, and is calculated to be over $2 million in FY2021.
My strength is Translational Research in Stem Cell/Cancer Stem Cell Biology/Therapy. I have authored over 170 manuscripts and my research has been published in Nature, Nature Medicine, Cancer Cell, Nature Communications, JCI, PNAS, Blood and Transfusion among other journals. I am Associate Editor of the journal Transfusion and a member of the American Association of Blood Banks and National Blood Foundation Research and Education Trust boards of directors. I’ve submitted four other manuscripts (in revision) and a P01 as a program leader (four projects and three cores) to the NHLBI for review.
I was honored to receive the following awards and appointments:
I have been a researcher for more than 26 years and began my work at Cincinnati Children's in 2001.
MD: Autonomous University of Madrid, Spain, 1989.
Residency: Hematology and Hematotherapy, University of Alcala de Henares, Madrid, Spain, 1993.
PhD: Faculty of Medicine, University of Alcala de Henares, Madrid, Spain, 1996.
Hematopoietic stem cell proliferation and differentiation
Experimental Hematology and Cancer Biology, Cancer and Blood Diseases, Global Health
Virus-specific T cells for adenovirus infection after stem cell transplantation are highly effective and class II HLA restricted. Blood Advances. 2021; 5:3309-3321.
Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion. Science Translational Medicine. 2021; 13:eabb1069.
Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging. Science Advances. 2021; 7:eabg5733.
Inflammation rapidly recruits mammalian GMP and MDP from bone marrow into regional lymphatics. eLife. 2021; 10:e66190.
Antioxidant prevents clearance of hemostatically competent platelets after long-term cold storage. Transfusion. 2021; 61:557-567.
Virus-specific T-cell therapy to treat BK polyomavirus infection in bone marrow and solid organ transplant recipients. Blood Advances. 2020; 4:5745-5754.
FOXO activity adaptation safeguards the hematopoietic stem cell compartment in hyperglycemia. Blood Advances. 2020; 4:5512-5526.
Yap1-Scribble polarization is required for hematopoietic stem cell division and fate. Blood. 2020; 136:1824-1836.
Frozen Platelets-Development and Future Directions. Transfusion Medicine Reviews. 2020; 34:286-293.