Research digest: Easy to digest updates on articles published in high impact journals.
STEM CELLS in heart regenerative medicine has come to the forefront in recent years. Clinical trials attempting to demonstrate a protective effect with stem cell therapy after heart injury have had mixed success and the mechanisms by which these stem cells act is still debated.
Do they change into new contracting heart cells? Do they stop injured cells from dying? Could the effect be on the accessory cell types that help the contracting cells? A concrete understanding of stem cell activity in cardiac regenerative medicine is still lacking.
IN AN ELEGANT STUDY conducted by Jeffery Molkentin and colleagues at the University of Cincinnati (Vagnozzi et al., 2019), the investigators aimed to observe the mechanisms by which stem cells improve heart contractility. Eight-week-old male and female mice received an intracardiac injection of one two types of primary adult stem cells:
Fractionated bone marrow mononuclear cells (MNCs), which comprised of all major haemotopoietic lineages, and cardiac progenitor cells (CPCs), which expressed mesenchymal cell-surface markers but were negative for haemotopoietic cell markers. Alternatively, mice were injected with zymosan, a non-cellular and potent activator of the innate immune response (Pillemer et al., 1953) or with saline control. Each condition had 5 or 6 mice. The researchers identified that in uninjured mice, 2 and 6 weeks after injection, there were more endothelial cells at the injection site of zymosan-treated hearts, but not in hearts injected with MNCs, CPCs or saline.
THE RESEARCHERS THEN INJECTED MNCs, CPCs, zymosan or saline on each side of the infarct border in mice one week after cardiac ischaemic injury. Ventricular function was investigated by echocardiography. In each group, 10-13 mice were used. Crucially, the researchers demonstrated that MNC-, CPC- and zymosan-treated groups all had significantly greater left ventricular function compared to saline control and this beneficial effect was present for at least 8 weeks. Treatment with an immunosuppressant cyclosporine A abolished the restorative effects.
Building on this knowledge, they investigated the extracellular matrix content in the peri-infarct border zone and identified a decrease with injection of MNCs as well as non-viable MNCs. This suggests that the effects are primarily due to immunoreactivity – and not to active paracrine signalling from the cells.
THIS SHOWED that the beneficial effects of adult stem cells is not through regeneration of the heart or by making new heart cells. “Injecting living cells, dead cell debris or even substances that induce inflammation all uniformly provide minor healing benefit to the heart by inducing an acute innate immune response that augments infarction healing properties and scar dynamics,” concluded Molkentin.
ALTHOUGH the important mechanisms in stem cell therapy are still yet to be fully understood, this study does show that “stem cell therapy can improve cardiac function after infarct injury in mice but not by the mechanisms proposed >15 years ago”.
THERE IS STILL A LOT that needs to be unravelled in stem cell therapy. However, it is widely agreed that there is huge potential for the use of stem cells in medicine and our understanding of the way they behave is getting clearer by the day.
Vagnozzi, R.J., Maillet, M., Sargent, M.A. et al. An acute immune response underlies the benefit of cardiac stem cell therapy.Nature 577, 405–409 (2020).
Pillemer, L., Blum, L., Pensky, J. & Lepow, I. H. The requirement for magnesium ions in the inactivation of the third component of human complement (C′3) by insoluble residues of yeast cells (zymosan). J. Immunol. 71, 331–338 (1953)
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