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Northwestern University Feinberg School of Medicine
Research

Faculty Profile: Douglas W. Losordo, MD

Douglas W. Losordo, MD

What are your research interests?
My scientific and clinical research activities are focused on the field of regenerative medicine with a particular emphasis on ischemic tissue repair. In the laboratory, we study molecular, cellular, biochemical, and physiological aspects of ischemic injury and evaluate different methods for intervening in the repair process that ensues naturally after an ischemic insult. Most recently, our clinical efforts have revolved around the use of autologous endothelial progenitor cells (EPCs) to improve perfusion and alleviate symptoms in patients with chronic ischemic conditions.

What made you pursue this type of research?
Soon after the discovery of angiogenic growth factors, evidence began to emerge that stimulating angiogenesis could lead to improved function in ischemic tissue. At the time, I was working in the laboratory of the late Dr. Jeffrey Isner, and we began studying the basic mechanisms and therapeutic possibilities for stimulating angiogenesis in ischemic tissue. This work began using a gene-therapy approach. In the late 1990s, the Isner lab described the first evidence for the existence of EPCs, and our laboratory’s focus gradually began to shift to the use of these cells in patients. Along the way, we have also studied the basic mechanisms that confer a progenitor phenotype on certain cells and have studied certain developmental pathways associated with blood vessel and cardiac development. Some of these pathways have been useful in our attempts to recapitulate tissue formation for therapeutic purposes.

What are some of your current research projects?
There are several exciting projects in the lab right now but because of space I can only mention a few:
Joern Tongers, a post-doctoral fellow from Hannover, Germany is evaluating Retention and maintenance of progenitor cells in the ischemic target region by bioactive, self-assembling nanofibers. This project investigates whether the use of a peptide amphiphile (PA) nanofiber matrix can increase the potency of cell therapy for treatment of ischemic cardiovascular disease by overcoming the low retention and viability of EPCs in ischemic tissue. Initial experiments will assess EPC proliferation, apoptotosis, viability, adhesion, migration, differentiation, and tube formation when cultured in the presence of PA nanofibers. Subsequent experiments performed in a murine model of hind-limb ischemia will assess the influence of PA nanofibers and cell therapy on vascular regeneration in vivo.

Koichi Kobayashi, a postdoctoral fellow from Japan is studying Cardiogenesis by wnt-11 gene therapy in acute myocardial infarction. This project is designed to determine whether gene therapy with the wnt-11 plasmid enhances recovery from myocardial infarction by inducing the differentiation of progenitor cells into cardiac cells. Progenitor cells will be mobilized from the bone marrow by G-CSF administration in a myocardial infarction model, and wnt-11 gene therapy will be administered locally. Subsequent assessments will identify the presence and lineage of mobilized cells in the ischemic myocardium.

Marie-Ange Renault, a post-doctoral fellow from Bordeaux, France is studying Angiogenic activity of sonic hedgehog via rho kinase–dependent MMP-9 and osteopontin expression. This study characterizes the molecular mechanisms involved in Shh-induced angiogenesis, specifically, the effect of Shh on endothelial cells. In vitro analyses assessed the effect of Shh treatment on proliferation, migration, tube formation, the expression of a variety of pro-angiogenic factors (VEGF, Ang1, bFGF, SDF-1a, MMP-9, osteopontin), and the activation of Gli transcription factors or the Rho signaling pathway. The potential involvement of MMP-9, ostepontin, and the Rho signaling pathway during Shh-induced angiogenesis was investigated in vivo by implanting pellets containing Shh, a Rho kinase inhibitor, or saline in the corneas of wild-type, MMP-9-null, or osteopontin-null mice.

Haruki Sekiguchi, a postdoctoral fellow from Tokyo Japan is studying the role of neural stem cells, the Shh pathway, and estradiol during nerve regeneration. This project investigates how estradiol influences the Shh pathway in neural stem cells during nerve regeneration. Neural stem cells were isolated from mice that constitutively express b-galactosidase or LacZ and administered with or without estradiol in wild-type mice after experimental nerve crush injury. Assessments included measures of intraneural angiogenesis and motor conduction velocity, and histological identification of labeled cells in regenerating tissues. Differentiation of neural stem cells was assessed by staining labeled cells for expression of endothelial (CD31)-, and Schwann (S100)-cell markers. Activation of the Shh pathway was determined by measuring the expression of Shh-dependent genes.

Why did you choose Northwestern University Feinberg School of Medicine?
Northwestern offered a great opportunity to expand the scientific horizons of the laboratory and to enter a dynamic, collegial environment. The University also affords great translational opportunities for our work because of the close relationship between the clinical departments and the research programs.

What is the biggest challenge you have experienced so far?
Almost every day that I have been on campus, I have discovered individuals or laboratories working in areas that are very complimentary to the work that we are doing, so a major challenge has been taking full advantage of all the opportunities for cross pollination throughout the Chicago and Evanston campuses.

What do you see for the future?
This is a very exciting time at Northwestern. Expansion of research has both broadened and deepened the expertise on our campuses, and the renewed focus on translational medicine provides Northwestern with a unique opportunity to capitalize on some of its strengths. There is quite a buzz about Northwestern around the country, and I expect that the near future will see a continuation of the track record of recruiting talented individuals to this campus. I think Northwestern is destined to become one of the leading centers in the field of regenerative medicine as our strength in biology, medicine, and engineering coalesce.

For more about Dr. Losordo and FCVRI, visit http://www.fcvri.northwestern.edu/