Extensive lit review performed on harnessing stem cells to generate biological pacemakers.


Irreversible degeneration of the cardiac conduction system is a common disease with high rates of mortality. While electronic pacemakers provide effective treatment, alternative approaches are needed with long-term implanted hardware proving undesirable.  Also, current pacemakers are limited by their artificial nature. For example, their parts can fail or they can become infected. In addition, the devices require regular maintenance, must be replaced periodically, and can only approximate the natural regulation of a heartbeat.

In contrast, biological pacemakers comprise electrically active cells that functionally integrate with the heart.  Theoretically, biological pacemakers, which are composed of electrically active cells that can functionally integrate with the heart, could provide natural heart rhythm regulation without the need for indwelling hardware.  Recent findings on cardiac pacemaker cells (PCs) within the sinoatrial node (SAN), along with developments in stem cell technology, have opened a new era in biological pacing.  Now, researchers at the University of California, San Francisco have performed an extensive literature review to investigate these approaches indepthly, addressing the potential for clinical translation.  The team state that their findings highlight the promise and limitations of new methods based on stem cell and reprogramming technologies to generate biological pacemakers that might one day replace electronic pacemakers.  The opensource review is published in the journal Trends in Molecular Medicine.

Previous studies show that cardiac electrical impulses originate in the SAN, a 2–3-cm-long comma-shaped structure at the junction of the superior vena cava and right atrium. During each heartbeat, the impulse generated in the SAN is transmitted to the neighboring right atrial myocardium. However, under a variety of common pathological conditions, irreversible degeneration or malformation of the cardiac conduction system results in slow heartbeat, activity intolerance, fainting, or even death. At present, there are no drugs appropriate for long-term use that can safely increase heart rate, so the only available treatment is electronic pacemaker implantation. In the USA alone, over 200 000 pacemakers are implanted annually, most commonly for degeneration and malfunction of the SAN.  The SAN contains approximately 10 000 specialized PCs. Several decades of basic research into the electrophysiological mechanisms involved in PCs automaticity resulted in the identification and cloning of the molecular correlates of critical PC ionic currents. With the ability to introduce exogenous genetic material into human cells in vitro and in vivo, there is an ongoing line of research aiming to transform normally quiescent areas of the heart into biological pacemakers.

The researchers state that their lit review shows recent attempts to create a biological pacemaker have leveraged these new discoveries on SAN molecular and developmental biology. One approach has been to use molecular markers identified in embryonic PC precursor cells to isolate and expand populations of PC progenitors from mixed populations of embryonic stem cells or reprogrammed cardiomyocytes in vitro. Ultimately, this selected population of cells would be expanded and transplanted into the heart to functionally couple with host myocardium. A second approach has been to drive expression of transcriptional regulators in non-PCs to direct differentiation into PCs, or to effect direct reprogramming from a non-PC to a PC. Theoretically, this approach could be applied to embryonic stem cells, induced pluripotent stem cells, or another somatic cell type with a view towards cell transplantation. Alternatively, this approach could be used as gene therapy to deliver a reprogramming cocktail directly to the diseased heart to convert resident quiescent cells into PCs.

The lab note that initial large animal studies on biological pacemakers have generated promising results, however, much more work remains ahead before biological pacing can be actually considered a clinically viable therapy. They go on to add that, for example, researchers need to better understand the mechanisms controlling the development and maintenance of pacemaker cells in the sinoatrial node, just as they must develop ways to compare experimental biological pacemaker tissue with bona fide sinoatrial node tissue. The group conclude that researchers will need to improve the methods used to deliver cells to desired locations within the heart, as well as the recovery of individual cells for detailed characterization and functional analyses.

The team surmise that biological pacemakers must meet a very high standard of performance to supplant electronic pacemakers, as even a few seconds without a heartbeat can lead to serious consequences.  For the future, the researchers state that it remains to be determined whether this will be technically feasible. They go on to add that despite such challenges, the field is poised for rapid progress over the next few years.

Source: University of California, San Francisco

 

Can Pacemaker-Like Cells be Derived or Programmed from Non-Pacemaker Cells?  This model figure displays several strategies to create a biological pacemaker through derivation of pacemaker cells (PCs) from fibroblasts, pluripotent cells, or resident cardiomyocytes, as enumerated in Table 1 (main text). First, patient-derived fibroblasts could be cultured and directly reprogrammed to PCs using multifactor cocktails, or via Gata4, Mef2C, Hand2, Tbx5 (GMHT) induction. Subsequently, selection for Hcn4 expression and for contractile apparatus could ensue. Alternatively, pluripotent cells [embryonic stem (ES) cells or induced pluripotent stem cells (iPSC)] could be programmed with PC-specific transcriptional regulators, or differentiated into cardiomyocyte progenitors with subsequent selection for PC-like cells. Finally, viral vectors could be delivered directly into the heart, attempting to reprogram resident cardiomyocytes into PCs in vivo.  New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development.  Vedantham et al 2015.

Can Pacemaker-Like Cells be Derived or Programmed from Non-Pacemaker Cells? This model figure displays several strategies to create a biological pacemaker through derivation of pacemaker cells (PCs) from fibroblasts, pluripotent cells, or resident cardiomyocytes, as enumerated in Table 1 (main text). First, patient-derived fibroblasts could be cultured and directly reprogrammed to PCs using multifactor cocktails, or via Gata4, Mef2C, Hand2, Tbx5 (GMHT) induction. Subsequently, selection for Hcn4 expression and for contractile apparatus could ensue. Alternatively, pluripotent cells [embryonic stem (ES) cells or induced pluripotent stem cells (iPSC)] could be programmed with PC-specific transcriptional regulators, or differentiated into cardiomyocyte progenitors with subsequent selection for PC-like cells. Finally, viral vectors could be delivered directly into the heart, attempting to reprogram resident cardiomyocytes into PCs in vivo. New Approaches to Biological Pacemakers: Links to Sinoatrial Node Development. Vedantham et al 2015.

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