The Center is motivated by the promise that this research will improve health and give hope to those with debilitating diseases. The recognition of the role of adult stem cells in vessel formation and tissue repair is pointing the way to their applications in diseases that involve insufficient blood flow. Indeed, several groups are conducting research studies in these areas.
Research & Scholarly Activities
Project 1: Completion of the Phase I/II clinical trial, “Stem cell Angiogenesis to promote limb salVagE (SAVE).
This phase I/II open- label single center trial, designed and implemented with assistance of VC-CAST support, enrolled and treated 32 patients with critical limb ischemia with autologous bone marrow mononuclear cells (ABMNCs). Results demonstrated that ABMNCs are a safe and potentially effective treatment modality for CLI in preventing amputation. The study is the result of the collaboration of the division of Cardiology (Keith March, MD, PhD, Pat G’sell, RN), Vascular Surgery (Michael Murphy, MD, Michael Dalsing, MD, Janet Klein, RN) and Hematology (Rafat Abonour, MD). Importantly, this study has prompted the development an efficient network of facilities and personnel to conduct multiple planned additional clinical trials using adult stem cells for regenerative therapies on the IUSoM campus and at the VA Medical Center. One of the first of these trials is expected to be a direct extension of this SAVE Phase I trial: a phase II randomized trial has been designed and has met with favorable feedback from the FDA. Other near-term trials are indicated below as goals of projects 5, 6, and 7.
Project 2: Isolation and Characterization of Endothelial and Mesenchymal Stem Cells from Term Human Placenta.
This investigation was launched in 2008 with the objective of isolating stem cells from human placenta that would be applicable in cell therapies to promote angiogenesis. This investigation involved the collaboration of Murphy (Surgery), Traktuev (Medicine), Saadatzadeh (Surgery), and March (Cardiology).
Project 3: Isolation and Characterization of Endothelial Colony Forming Cells (ECFCs) from Human Adult Blood Vessels.
Highly proliferative endothelial stem cells were isolated from human arteries and leg veins by Murphy, using colony forming assays developed by David Ingram, MD and Merv Yoder, MD (collaborators in Pediatrics). The significance of this study is that (1) we have developed the ability to isolate these cells from vessel endothelium, a critical step in the analysis of ECFCs in the pathogenesis of disease; and (2) we have shown that autologous vein, potentially available by minimally invasive harvesting methods, can provide a practical source of ECFCs that are available for autologous use in cell therapies.
Project 4: Loading of Human Adipose Stromal Cells (hASCs) and Saphenous Vein EPCs (SVEPCs) with Magnetic Nanoparticles.
In collaboration with Robert Levy, MD, PhD of the Children’s Hospital of Pennsylvania, this study is testing the feasibility of loading magnetic nanoparticles into progenitor cells; this would permit the use of magnetic fields to direct cells more efficiently to target organs. This study involves a collaboration of Murphy, March, Saadatzadeh, and Kyle (Medicine).
Project 5: Adipose Stem Cells for Peripheral Arterial Disease.
We are working with the FDA as well as a corporate partner, Tissue Genesis, to test the feasibility and safety of providing adipose (fat) stem cells (ASCs) in patients with severe peripheral vascular disease. Animal trials that we have conducted have suggested that ASCs are very potent in this regard; multiple other labs have also corroborated these data. We would like to be the first to complete testing of this concept in a human Phase I critical limb ischemia trial essentially identical in design to the ABMNC “SAVE” study (Project 1).
Project 6: Endometrial Regenerative Cells for Peripheral Arterial Disease.
We are collecting specimens from donors at the IUSoM for the procurement of Endometrial Regenerative Cells (ERCs) for the purpose of expansion and use in preclinical and clinical studies. ERCs will be used in animal models of hindlimb ischemia, acute ischemic stroke, and spinal cord injury. Our ultimate intent is to test ERCs in a CLI trial identical in design to the ABMMNC study “SAVE”.
Project 7: Adipose Stem Cells for treatment of Heart Attack and prevention of Heart Failure.
Based on our prior findings that adipose stem cells could protect leg tissue from injury due to poor blood flow, we wished to test the possibility that heart tissue would be protected in a similar way. We also have obtained data that the factors secreted by ASCs could protect nerves from injury due to low oxygen as well as other injurious factors that mimic degenerative conditions of nerves, and we hypothesized that this in turn could contribute to cardiac functional preservation. Indeed, we found that rats with heart attacks had less damage and more nerve sprouting following ASC injection. In a study of ASCs infused into normal pig coronary arteries, we also found that ASCs could self-aggregate, creating the possibility of microvascular obstructions and undesirable injury. We discovered that this problem could largely be avoided by the admixture of heparin and other selected agents with the ASC prior to infusion. This finding is potentially very important in directing future studies of ASC delivery into heart tissues. This project has involved collaborations among March, Johnstone, and Chen.
Project 8: Adipose Stem Cells for Emphysema and other Lung Diseases
We reasoned that adipose-derived stem cells express several critical determinants of lung rejuvenation, which may provide components necessary for tissues to recover from lung injury, such as that induced by cigarette smoke (CS) in emphysema. We (Petrache, March, Schweitzer, Johnstone, and others) have evaluated the therapeutic effects of ASCs on CS-induced lung injury. Mice receiving ASCs were protected against CS-induced alveolar space enlargement. We have filed a patent for this work via the IURTC.
Project 9: Adipose Stem Cells for Prevention and Treatment of Diabetes
We (Evans-Molina and March) have obtained data that will make the transplantation of islets for the long-term cure of diabetes in selected patients more possible than ever before. In addition, the work of VC-CAST in the area of diabetes has attracted the partnership of the R.B. Annis Foundation.