Human heart tissue has minimal ability to regenerate following injury. But the protein Fstl1, which is normally expressed in the heart's epicardial region, has now been shown to induce regeneration following heart attack. See Article p.479
Healthy mammalian heart tissue has a measurable but limited ability to regenerate1. Over a normal human lifespan, around 45% of heart-muscle cells (cardiomyocytes) are renewed, with the remaining 55% persisting from birth. This rate is not sufficient to repair the injury caused by myocardial infarction, or heart attack as it is commonly known. Instead, the infarcted area becomes populated by fibroblast cells, which form a non-contractile collagenous scar — a quick fix that progressively decreases the heart's pumping capacity. Any regenerative therapy must thus provide an influx of cells that can properly heal the muscle, either from an external source or from the body itself2. A major effort3,4 is going into the potential use of immature cardiomyocytes derived from human stem cells for such regeneration. But in this issue, Wei et al.5 (page 479) take a different approach, making use of a protein that is present in the epicardial region of a healthy heart but lost following heart infarction.
Previous work documented that the protein follistatin-like 1 (Fstl1) is involved in the development of many organ systems, by binding to proteins of the transforming growth factor-β (TGF-β) family and inhibiting their functions6. Fstl1 is also involved in a spectrum of diseases, from heart attacks to arthritis, lung fibrosis and cancer, through its activation of multiple signalling pathways and inflammatory and immune responses. Depending on the organ system, Fstl1 can act as a proinflammatory molecule7 or a cell-protective factor8, or can induce immune responses6.
Fstl1 is also known as a modulator of cardiac development9 and as a marker of heart ischaemia (restricted blood supply), hypertrophy (abnormal enlargement) and end-stage heart failure8. The many roles of Fstl1 are seemingly contradictory: it protects cardiomyocytes from apoptotic cell death and hypertrophy by mobilizing signalling through the phosphorylated kinase enzyme AMPK, but it suppresses their differentiation from stem cells by inhibiting signalling of the TGF-β family member BMP. Notably, the presence of Fstl1 in the heart correlates with reduced infarct size and with functional recovery, but this effect has been ascribed to enhanced reformation of blood vessels (revascularization) and cell survival, rather than the formation of cardiomyocytes10.
Wei et al. now provide new and counterintuitive insights into the biological functions of Fstl1. Their study shows that, in the healthy heart, the protein is expressed in the epicardium, the membranous layer surrounding the myocardium, throughout development and in adult life. They also observed that heart infarction causes Fstl1 expression to be transferred from the epicardium to the myocardium, and that this shift impairs the heart's regenerative ability. Remarkably, the study reveals that re-established expression of epicardial Fstl1 can regenerate the injured heart muscle.
The investigators hypothesized that a patch releasing epicardial Fstl1, when placed onto the heart infarct, would serve as a source of Fstl1 and stimulate proliferation of the resident cardiomyocytes (Fig. 1). To test this hypothesis, they loaded collagen patches either with medium containing Fstl1 in which epicardial cells had been cultured, or with human Fstl1 purified from a bacterial protein-expression system, and sutured these to the hearts of mice that had undergone modelled myocardial infarction. Four weeks later, they observed more cardiomyocytes, higher transcription of cardiac marker genes and a greater frequency of calcium pulses (indicative of heart pumping) compared with infarcted hearts without patches. There was also less formation of fibrotic scar tissue and a better revascularization of the area. These findings suggest that such in situ manipulation might allow control of the fate of existing cardiomyocytes, to achieve heart regeneration without implanting cells.
This study is an inspiring example of how a developmentally conserved regulatory pathway can be mobilized to induce heart regeneration. Although more work needs to be done to determine the benefits of such an approach in large-animal models (the authors conducted a preliminary study in pigs, but it involved only six animals divided into three groups), the proposed reconstitution of epicardial Fstl1 could lead to entirely new modalities for treating heart infarction. The study also leaves us with questions about the biological phenomena responsible for the observed effects. Fstl1 is still an enigmatic protein with largely unknown properties, but with seemingly huge potential for diagnosing and treating heart disease.
One intriguing question is why infarction-induced myocardial expression of Fstl1, or even experimentally induced overexpression of Fstl1 in the myocardium, cannot induce heart regeneration, but epicardial Fstl1 applied on the patch can. The authors also find this result paradoxical. They suggest that different extents of glycosylation (the number of carbohydrate molecules — glycans — attached to the protein) that they measured for epicardial and myocardial Fstl1 reflect differences in glycan structure that affect the proteins' function. It remains to be seen whether these differences are cell-of-origin specific, how important glycosylation is for regenerative ability, and what the necessary features would be for a patch that can induce regeneration in the human heart.
Other questions arise from the combined observations that, although myocardial Fstl1 does not induce cardiomyocyte generation, it does protect immature cardiomyocytes, whereas epicardial Fstl1 on a patch enhances cardiomyocyte proliferation, but is not cell-protective. Further investigation is needed to explore whether glycosylation is a key determinant of cardioprotective versus cardiogenic effects, as proposed by Wei and colleagues. Finally, the study suggests that only very immature cardiomyocytes respond to Fstl1. The genetic signatures and the origin of the responsive cells (whether they are resident or recruited) also remain to be determined.
These questions are likely to motivate future studies. Exciting approaches are now emerging at the interface of stem-cell biology and tissue engineering. High-fidelity models of human heart tissue, combined with findings such as these, could markedly advance quantitative biological research and the clinical translation of discoveries into curative treatments for heart disease.Footnote 1
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Vunjak-Novakovic, G. A protein for healing infarcted hearts. Nature 525, 461–462 (2015). https://doi.org/10.1038/nature15217
Transplantation of human villous trophoblasts preserves cardiac function in mice with acute myocardial infarction
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