Cell therapy without cells

Researchers at Columbia University, working under the guidance of Professor Gordana Vunjak-Novakovic, have developed an innovative technique for using extracellular vesicles secreted by cardiomyocytes derived from human pluripotent stem cells to regenerate damage to the heart muscle.

Heart disease is one of the most important health problems and ranks first among the causes of death worldwide. The human heart is not capable of self–regeneration of damage, and the death of cardiac muscle cells – cardiomyocytes - irreversibly weakens the heart and limits its ability to pump blood through the body.

For quite a long time, researchers have been actively working on methods of stem cell transplantation to replace dead cardiomyocytes and restore cardiac function, but experiments have demonstrated low survival of implanted cells and their inability to differentiate into cardiomyocytes. Preimplantation differentiation of stem cells into cardiomyocytes provided an improvement in cardiac function, but was accompanied by the development of complications: the reduction of implanted cells was not synchronized with the contractions of the heart, which led to potentially fatal arrhythmias.

Taking as a basis the hypothesis confirmed by the results of many clinical studies, according to which most of the implanted stem cells are excreted from the body within a few hours after administration, but at the same time has a positive effect due to the release of regulatory molecules, the authors proposed to use not cardiomyocytes themselves, but extracellular vesicles secreted by them to repair damage to the heart muscles.

Almost all cells of the body secrete and absorb vesicles – membrane vesicles filled with various molecules that affect the cells that absorb them. In fact, vesicles are a kind of "parcels" that are exchanged among themselves not only by cells located in close proximity, but also by cells distant from each other. Vesicles secreted by cells are easily isolated from the culture medium and can be stored frozen for a long time.

Such a ready-made "medical product" has a number of advantages over preparations from living cells:

• it can be used for emergency care, unlike live cells, which may take more than one month to isolate and cultivate;
• it does not cause the development of arrhythmia and
• the mechanism of its introduction into clinical practice is much simpler than the mechanism of introduction of cell therapy methods.

To test their hypothesis, the authors obtained cardiomyocytes from human adult stem cells and cultured them long enough for the cells to secrete a large number of extracellular vesicles. For comparison, they used vesicles secreted by undifferentiated stem cells. The results obtained using the latest generation sequencing method showed that only the vesicles of differentiated cardiomyocytes contained cardiogenic and vasculogenic (promoting the growth of blood vessels) microRNAs, which are powerful regulatory molecules.

Such vesicles were placed inside collagen capsules, ensuring their slow release for four weeks, which were implanted into damaged areas of the heart of a rat model of myocardial infarction. After that, the researchers monitored the work of the animals' hearts, registering indicators of the pumping function of the heart and any arrhythmic manifestations.

The observations obtained showed that, compared with the implantation of living cells, the introduction of extracellular vesicles not only caused the development of arrhythmia much less often, but also provided a more effective restoration of cardiac function. In fact, after 4 weeks of vesicle therapy, the cardiac function of the experimental group animals was comparable to the cardiac function of the control group rats.

Recovery of the heart muscle after a month of extracellular vesicle therapy. 
Immune labels: agglutinin (red), troponin (green) and DAPI (blue).
Gordana Vunjak-Novakovic/Columbia Engineering.

In the near future, the authors plan to study changes in the properties of extracellular vesicles as cardiomyocytes obtained from pluripotent stem cells mature and determine the optimal degree of their maturity for clinical use. In addition, they are studying the specific mechanisms provided by the therapeutic effects registered during the study.

Article by Bohao Liu et al. Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells is published in the journal Nature Biomedical Engineering.

Evgenia Ryabtseva, portal "Eternal Youth" http://vechnayamolodost.ru based on materials from Columbia University: New Cell Therapy Aids Heart Recovery—Without Implanting Cells.