Pim-1 Enhanced Adult Cardiac Stem Cells: Clinical Therapy for Myocardial Regeneration
Heart attack leads to death of a portion of the heart wall. Dead cells cannot contribute in the pump function of the heart, which leads to exhaustion of the remaining healthy parts of the heart muscle upon time and results in heart failure. Patients with heart failure eventually need heart transplantation to survive. There are two ways to help patients with a very weak heart: prevent them from getting a heart attack or make sure that the dysfunctional part of the heart wall starts contributing in the heart function by making new cells that replace dead cells
Over the years, a lot of time, research, effort, education and money have been spent on preventing patients from getting a heart attack. However, despite reduction of risk factors, heart disease is the number one cause of death in the United States. The second option is to replace dead cells with newly formed cells that are contributing to the pump function of the heart thereby preventing exhaustion of the remaining healthy part. In every organ, there is a continuous manufacture of newly formed cells. The source for this new cell formation is their stem cell population. Stem cells are very primitive “naïve” cells that can stay “young” and uncommitted and replicate themselves more than mature cells. The heart has a source of stem cells too, the so-called Cardiac Progenitor Cells (CPCs). This resident source of “naïve” cells is meant for replacement of cells with natural aging, which is a gradual process and requires a modest manufacture for cell replacement. In contrary, cell loss upon a heart attack is massive and requires a robust cell replacement machinery. Although the CPCs try to replace some of the dead cells after a heart attack, they become overwhelmed by the amount of work that they have to perform and run out in their replicating capacity.
In order to make new cells in the heart after a heart attack, we want to isolate these “weak” stem cells from the heart and use “doping” to increase their capacity to divide and survive. How to “dope” stem cells? Proteins dictate a cell whether to live, die, divide, commit to a certain cell type or stay uncommitted. Modifying and manipulating certain specific proteins in a cell can influence cellular processes. Our group has identified the protein Pim-1 in the heart, where it plays an important role in cell division, survival and commitment towards heart cells. Modifying stem cells with higher level of Pim-1 is an ideal “doping” for our heart stem cells. We obtain human stem cells from heart failure patients and modify them to have higher Pim-1 levels. These cells are then injected into the heart to form new muscle and improve cardiac function. Early results in animal models show that Pim-1 cells make a significant difference in heart function and new cell formation compared to unmodified cells. The purpose of this proposal is to take this approach from the laboratory to where it is needed, a patient’s bedside.
Heart disease is the leading cause of death in California (By Laura E. Lund, M.A.1 and Nan Pheatt, M.P.H. Center for Health Statistics). In addition, heart disease is a major cause of chronic illness in California. This strains California’s health care system and its economy, as well as the emotional and financial resources of families. It is clear that action is needed now to halt the consequences of heart disease. Clinical application of engineered stem cells opens a new field in the industry, thereby creating new employment opportunities. In an academic setting, this field of research can be a source of knowledge and educating young scientists in the field. In addition, stem cell therapy and its clinical application is not only essential in the heart but also in other organs. Cell based therapy can be useful in a variety of patient populations suffering from chronic illness due to e.g diabetes, spinal cord injury and Parkinsons. Improvement of their quality of life and survival will lead to contribution to the society and economy of the state of California. Should this technology become implemented in clinical trial, hospitals in our state will be engaged to enroll their patient population, thereby offering cutting edge cellular cardiomyoplasty to Californians that will be the best therapeutic option in the country. California will become known nationally as the destination for treatment of advanced heart failure, thereby raising both research and clinical profiles of cardiac care and attracting new researchers and clinician to work in our State. The successful implementation of this therapeutic approach will also stimulate research at State colleges and universities, translating into more federal funding for regenerative medicine research in our State and a logical transition from CIRM to subsequent support by federal government and the biotech / pharmaceutical industry. The eventual impact is to bring the best treatment for heart failure to our State, together with the best scientists and clinicians working together to rapidly translate their work into deliverable patient care that will accelerate and become self-sustaining by infusion of capital from multiple sources, creating a revenue stream that will reward CIRM investment and perpetuate the initial advances underwritten by this proposal.