Grant Award Details
Induction of Pluripotent Stem Cell-Derived Pacemaking Cells
- The goal is to increase the yield of pacemaking cells that can be differentiated from human induced pluripotent stem cells (hiPSCs). There is an emphasis on Ca2+ signaling pathways via activation of small conductance Ca2+-activated K+ channels (SKs).
This goal of this project is to improve the yield of pacemaking cells from human induced pluripotent stem cells (hiPSCs) that can be used to engineer biopacemaker. We have demonstrated that manipulation of the membrane potential of hiPSCs using small molecules can upregulate genes of the desired cell type progressing to the pacemaking cells at all differentiation stages. In the differentiation stage to mesodermal cells, treated hiPSCs exhibit a membrane potential that is further down the differentiation path than untreated control. This source was this change was examined.
We continued our work in improving the yield of pacemaking cells from human induced pluripotent stem cells (hiPSCs) that can be used to engineer biopacemakers. The ion channel isoform responsible for the induced membrane potential changes in hiPSCs and their differentiating cardiac progeny was determined. We focused on optimizing the duration and the timing of membrane potential manipulation in improving the efficiency of pro-pacemaking cardiac progenitor cells and pacemaking cells.
Since the last reporting period, we have determined that pharmacologic activation of small conductance Ca2+-activated K+ (SK) channel in specific differentiation stages of human induced pluripotent stem cells (hiPSCs) can improve the yield of a population of cardiac progenitor cells that are precursors to pacemaking cardiomyocytes. This effect was mediated through calcium release from an intracellular calcium store. Activation of SK channels after the cardiac progenitor stage also increased the frequency of automaticity in hiPSC-derived cardiomyocytes, which is a hallmark of pacemaking cardiomyocytes.
In this reporting period, we verified the role of small conductance Ca2+-activated K+ (SK) channels in intracellular Ca2+ release by demonstrating the co-localization of the SK channels with receptors mediating Ca2+ release from the intracellular store. We have also demonstrated that the observed increase in the number of hiPSC-derived cardiomyocyte with fast pacemaking frequency induced by SK activation may be due to an increase in the number of cardiomyocytes with a fast Ca2+-clock that drives the pacemaking function. With additional small molecules, we have improved the cardiomyocyte yield over the most efficient published protocol that regulates the Wnt pathway.
Grant Application Details
- Induction of Pluripotent Stem Cell-Derived Pacemaking Cells
Currently, over 350,000 patients per year with abnormal heart rhythm receive electronic pacemakers to restore their normal heart beat. Electronic pacemakers do not respond to the need for changing heart rate in situations such as exercise and have limited battery life, which can be resolved with biopacemakers. In this proposed project, we will examine methods that improve the generation of pacemaking cells from human induced pluripotent stem cells as candidates for biopacemaker.
Statement of Benefit to California:
This proposal aims to generate pacemaking cells through facilitated differentiation from human induced pluripotent stem cells that may serve as biopacemakers. Over 350,000 patients a year in the U.S. require the implantation of an electronic pacemaker to restore their heart rhythm, with more than 3 million patients that are dependent on this device. At the cost of $58K per pacemaker implantation, the healthcare burden is greater than $20 billion a year. However, the cost associated with these electronic devices does not end with surgery for implantation. These devices require a battery change every 5 to 10 years that involve another surgical procedure. With California being the most populated state, this can be very costly to the Californians. It also does not give the patients the quality of life by having to endure repeated surgeries. The possibility of biopacemaker that requires no future battery replacements and other advantages such as physiological adaptation to the active state of the patient make biopacemakers a truly desirable alternative to electronic devices. Moreover, one in 20,000 infants or preemies with congenital sinoatrial node dysfunction are also inappropriate candidates to receive electronic pacemakers because they are physically too small and require a proportional increase in the length of pacing leads with their significant growth rate. Therefore, there is a great need for biopacemakers that may overcome the deficiencies of electronic devices.
Source URL: https://www.cirm.ca.gov/our-progress/awards/induction-pluripotent-stem-cell-derived-pacemaking-cells