Mesenchymal Stem Cells Improve Heart Regeneration via Macrophage Polarization


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It is well known that the most commonly available forms of stem cell therapy produce benefits via signaling on the part of the transplanted cells, which soon die, rather than via any sort of integration of these cells into tissues. These treatments use varieties of what are called mesenchymal stem cells, which is actually a poorly defined, broad category. One clinic's mesenchymal stem cells are usually meaningfully different from those of the next. Nonetheless, these therapies fairly reliably reduce chronic inflammation. This can allow for improved regeneration in patients, but that outcome is much less reliable in practice.

The innate immune cells known as macrophages are important in the complex dance of tissue regeneration. In recent years researchers have become increasingly interested in deciphering and altering macrophage behavior, switching more of these cells from the aggressive and inflammatory M1 polarization, responsible for hunting pathogens, to the pro-regenerative M2 polarization. It is thought that aging is characterized by too much of a bias towards M1, and the balance might be forced back to M2 via the application of suitable therapies. It is perhaps not surprising that we should find that some existing therapies that can modulate inflammation and improve regeneration act through this mechanism.

Myocardial infarction (MI) is a major cause of coronary heart disease (CHD). More and more studies have shown that stem cells can play an important role in tissue repair and anti-inflammation. In particular, mesenchymal stem cells (MSCs) have shown anti-inflammatory and immunological functions. Indeed, MSCs have also been shown to have the potential to enhance the recovery and regeneration of the infarcted myocardium. The current belief on the role of MSCs in myocardial regeneration is their synthesis and secretion of cytokines and other trophic growth factors to signal to the injured myocardial cells, which may also involve anti-aging effects.

We have recently shown that the effects of transplantation of CD146+ MSCs on myocardial regeneration after MI exceeds the effects of transplantation of MSCs, likely resulting from reduction of aging-associated cellular reactive oxygen species in injured cardiac muscle cells (CMCs). Many effects of MSCs on tissue repair and cell regeneration are conducted through their crosstalk with macrophages. It is traditionally thought that macrophage are deemed to be white blood cells with a major functionality of swallowing and ingesting wastes, dying or dead cells, and impurities. Nevertheless, recently studies have shown that macrophages have much more functions other than phagocytosis. Therefore, a more complicated classification of macrophages has been applied, in which 2 subtypes of macrophages are distinguished by two phenotypes. One was named as "M1" macrophages, while the other alternatively polarized one was named as "M2" macrophages, which function in regulation of humoral immunity and promotion of tissue repair.

Since the role of macrophages in the MSC-mediated recovery of heart function after MI remains unclear, this question was thus addressed in the current study. We found that transplantation of MSCs did not alter the total number of the macrophages in the injured heart, but induced their polarization towards a M2-phenotype. Moreover, administration of TNFα into MSC-transplanted mice, which prevented M2-polarization of macrophages, abolished the effects of MSCs on recovery of heart function and on the reduction of infarcted cardiac tissue. Thus, our data suggest that MSCs may rejuvenate CMCs after ischemic injury at least partially through induction of M2-polarization of macrophages.