Innate Immunity in Nuclear Reprogramming
Our investigators advanced the field of stem cell therapy by showing that innate immune pathways are critical in the reprogramming process that changes somatic cells into induced pluripotent stem cells (iPSCs). We discovered that this beneficial innate immune response could be activated with small molecule agonists of TLR3 to enhance the efficiency of iPSC generation. This approach avoids integrating viral vectors, which limit therapeutic applications, and provides a method to efficiently generate therapeutic grade stem cells.
The center is developing methods for direct reprogramming to induce transdifferentiation of one somatic type cell into another cell type for therapeutic applications in healing. For example, fibroblasts migrate into areas of a myocardial infarction to form scars where heart tissue is damaged. If they could be transformed into endothelial cells at the site of damage, they could instead form the microvasculature needed to provide an environment that nurtures cardiac stem cells. This would improve healing with functional tissue, rather than with scar tissue.
The team is actively developing small molecules to induce human fibroblasts to transdifferentiate into endothelial cells. By combining these small molecules with nanotechnology-based delivery systems, the team is also enhancing this approach, by increasing the retention time. This optimizes the specificity of targeting to damaged tissue, and improves both pharmacokinetics and pharmacodynamics by fine tuning the sustained and controlled release parameters.
iPSC-ECs for Peripheral Vascular Diseases
The center has developed technology to rapidly and efficiently produce iPS endothelial cells (iPSC-ECs), which can generate capillaries and improve perfusion in models of peripheral arterial disease. The cells can be grown on nanopatterned collagen conduits, which were developed in collaboration with university and corporate partners. This results in grafts that have reduced inflammation during the healing process.
In a parallel study, nanopatterned collagen threads implants have been used to generate human lymphatic iPSC-ECs to treat lymphedema. This work is performed together with our corporate partner Fibralign, and it is supported by funding from the U.S. Department of Defense.
Extending the Telomere for Myocyte and EC Rejuvenation
Another approach to cardiovascular regeneration is to extend the telomeric DNA to increase the replicative capacity and function of the cell. The center has developed a modified mRNA approach to transiently express telomerase in human somatic and adult stem cells. This approach increases telomere length and enhances replicative capacity of the cells. Our novel mmRNA constructs were developed by Dr. Eduard Yakubov, who was the first to use RNA methodology to induce nuclear reprogramming. Dr. Yakubov directs the Houston Methodist Research Institute RNA Core, designated as the mmRNA core for the National Heart, Lung and Blood Institute (NHLBI) Progenitor Consortium.
Endothelial Regeneration and Nitric Oxide
Regulation of nitric oxide biology using small molecules can be used to create clinical therapies for the following
- diopathic pulmonary fibrosis
- chronic obstructive pulmonary disease (COPD)
- migraine headaches
- etastatic cancer peripheral arterial disease (PAD)
- pulmonary and systemic hypertension
- insulin resistance
Dr. Yohannes Ghebremariam directs the nitric oxide biology laboratory in the Center for Cardiovascular Regeneration. This lab focuses on the role of nitric oxide (NO)/dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis and progression of cardiovascular and pulmonary diseases. Fundamental understanding of the endogenous and exogenous factors that influence NO/DDAH biology is critically important for the discovery and development of novel therapeutics. The lab uses high throughput screening (HTS) technology to discover small molecules that regulate DDAH activity and production of NO. Small molecule activators of DDAH might have significant therapeutic potential for a number of cardiovascular diseases characterized by impaired DDAH activity and/or decreased production of NO. By contrast, diseases characterized by overproduction of NO (principally driven by inducible NOS) and/or overly active DDAH could be therapeutically modulated by small molecule inhibitors.
CD34+ BMMNCs for Peripheral Artery Disease
The center is participating in the CCTRN study to pursue clinical trials in adult stem cell therapy. The study is funded by the NHLBI, and includes seven national sites. The first clinical trial will assess the utility of bone marrow derived CD34+ mononuclear cells (versus placebo) for the treatment of patients with intermittent muscle pain during exercise due to PAD. The cell therapy will be assessed for pain reduction, enhancement function, and improved blood circulation.
Adult Stem Cells for Peripheral and Coronary Artery Diseases
The center is also pursuing industry-sponsored studies to assess adult stem cell therapy for intermittent muscle pain during exercise (intermittent claudication) and blockage of blood flow to the limbs (critical limb ischemia). The clinical research arm of the center pursues opportunities to work with industry to assist in the execution of other adult stem cell trials for peripheral or coronary artery diseases.
The center produces a seminar series called "Frontiers in Cardiovascular Sciences," which brings internationally recognized physicians and scientists to Houston Methodist. Additional educational events are offered in biotechnology and in device development and entrepreneurship. The center also provides project selection for seed grants and project guidance toward licensing or company formation, as well as collaborative training programs, including T32 and K12 programs to support postdoctoral training and mock study sessions for fellows and junior faculty who are submitting grants related to cardiovascular disease.