The study of stem cells in regenerative medicine is a growing field of basic and clinical research, generating a broad interest and debate in the scientific and the public communities. The ability to mobilise and activate endogenous stem/progenitor cells in diseased organs or to introduce exogenous stem cells for tissue regeneration/repair may positively impact many diseases. In this commentary, Massimiliano Gnecchi reviews the evidence base for stem cell therapy in treating heart disease.
Starting from the late 1990s, the regenerative capacity of a variety of multipotent adult stem cells (ASC) harvested from different tissue sources has been experimentally tested as a means to cure ischaemic heart disease and end-stage heart failure. Tissue regeneration from trans-differentiation of transplanted ASC was originally proposed as the principal mechanism underlying their therapeutic effects. Most importantly, the magnitude of cardiac regeneration described in the first experimental reports encouraged clinical investigators to rapidly test cell therapy in humans without further rigorous confirmations of the original data. Many clinical studies have been conducted with different cell types: skeletal myoblasts (SM), bone marrow-derived mononuclear cells (BM-MNC), mesenchymal stromal cells (MSC) and resident cardiac stem cells (CSC), to name but a few. Unfortunately, the efficacy results obtained so far are inconclusive, and cell therapy has never entered the routine clinical practice.
Lessons learnt
Despite this apparent failure, we have learned quite a few things from the first clinical trials, and these now well-established concepts must drive our choices when designing the new cell therapy protocols if we want to eventually succeed in repairing failing hearts. On top of that, more recent animal studies allowed us to better understand the main issues still hampering an effective translation from the promising pre-clinical results to the bedside. Among them, the most relevant are the low engraftment rate and the incapacity of the cells so far tested to efficiently differentiate into fully mature cardiomyocytes, resulting in the lack of heart regeneration, as said the original goal that scientists aimed to reach when they started testing cell therapy.
The issue of poor cell engraftment is common to all cell types tested in clinical trials: BM-MNC, MSC and CSC. Several approaches have been proposed to overcome this hurdle, from the overexpression of protective genes to cell preconditioning. More recently, administration of cells together with degradable biomaterials, or other tissue engineering techniques, have been tested in animal models with promising results. The incapacity to robustly differentiate into cardiomyocytes is also a problem shared by BM-MNC, MSC and CSC. Using the latest state of the art methodologies for cell fate tracing, several investigators have reported that there is no evidence of ASC differentiation in vivo and some of the earliest findings have been harshly criticised. Currently, scientists are considering couple of different approaches to overcome the issue of poor ASC differentiation: the implementation of pluripotent stem cells—such as embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC)—that are truly able to form myocytes or the development of effective strategies to potentiate the limited innate regenerative capacity of the heart.
Animal studies have also allowed us to clarify that the mechanism of stem cell action is mainly though production and release of soluble factors rather than direct cardiac regeneration, a concept that we pioneered in 2005 and subsequently confirmed by dozens of different labs worldwide. In particular, cardiac protection, improved angiogenesis and possibly endogenous regeneration, together with reduced scarring are the main effects mediated by the cell’s secretome. Proteins, exosomes and non-coding RNAs are the putative mediators of these positive paracrine effects. The demonstration that stem cells secrete therapeutic factors provides a potential breakthrough in that, rather than administering cells, one may be able to administer the whole secretome, the exosomes or even specific proteins. This approach opens new and unexplored therapeutic options, which present several advantages over the use of cell preparations.
Conclusion
The initial expectations regarding the capacity of stem cells to regenerate cardiac tissue were just too high since they were based on wrong interpretations of experimental findings and because the protocols used for administration were over-simplistic. However, the lessons learned from previous experiences will certainly help us to progress toward the development of more effective cell and molecular therapies to regenerate, or more realistically to repair, broken hearts.
Massimiliano Gnecchi is at University of Pavia, Pavia, Italy. He spoke about this topic at the European Association European Association for Cardio-Thoracic Surgery (EACTS) annual meeting (18–20 October, Milan, Italy).
