Treatment modalities for cardiovascular diseases have steadily progressed throughout many decades. To date, numerous medical-, surgical-, and catheter-based options are clinically available to improve patients’ quality of life, prolong survival, and reduce morbidity, mainly the development of clinically manifest heart failure.1 However, even though clinical results have steadily improved, the development of heart failure cannot be reliably prevented. This is owed to the fact that none of the currently available treatment options enable a reversal of the remodeling process after myocardial injury which is considered the holy grail of cardiac biology.
Cardiac cell therapy is aimed at restoration of cardiac function by the transplantation of cells which are aimed to exert a direct beneficial effect on the damaged myocardium. To date, compelling preclinical data exist that suggest that cell-based therapy may be a true game changer in regenerative medicine and therefore holds promise to revolutionize the treatment of heart diseases. Experimental cell based therapeutics can be—among others—broadly classified according to the following criteria: (1) the cell type(s) used and therefore the mechanism of action, (2) the route of cell administration, and (3) the cell source (eg, autologous or allogeneic). Accordingly, many different approaches have been and are currently under investigation.
In this issue of Transplantation, Mori et al2 investigated an alternative delivery method of human adipose-derived mesenchymal stem cells (ADSC) as a xenograft for treatment of ischemic cardiomyopathy. Human ADSCs mixed inside a defined fibrinogen-thrombin solution were sprayed onto the infarcted myocardium of pig hearts. Four weeks after transplantation, pigs treated with the human ADSC spray presented with significantly improved functional cardiac performance as well as beneficial effects on ventricular remodeling and vascularization 8 weeks after treatment compared with control animals. Furthermore, the coronary flow reserve was maintained, and increased levels of factors related to angiogenesis were found in the treated area. Notably, the pigs did not receive immunosuppression. No adverse events, such as arrhythmia, neoplasia, or procedure-related mortality, were observed.
Adipose-derived mesenchymal stem cells have been proposed as a suitable cell type candidate due to their ease of accessibility and their tentative cardioprotective paracrine effects.3 This cell type has been investigated in clinical trials in which safety and short-term efficacy were demonstrated. In accordance with these previous reports, the study by Mori et al similarly demonstrated a beneficial effect of ADSCs for treatment of myocardial infarction. As proposed by the authors, this effect is most likely owed to the paracrine activity of the transplanted cells. The authors nicely showed that ADSC transplantation was associated with a maintained ventricular wall thickness, reduced infarct area, less fibrosis, smaller cardiomyocyte diameter, and a greater capillary density compared with the control group. This resulted in improved functional performance at 4 weeks after treatment (improved left ventricular ejection fraction and left ventricular end systolic diameter). Even though the results demonstrated here are highly encouraging, the major limitation remains a lack of long-term retention—and therefore functional engraftment—of the transplanted cells, therefore questioning the longer-term efficacy of this approach. Mori et al showed that 8 weeks after transplantation, the transplanted cells seem to have completely vanished. Previous studies using intracoronary or intramyocardial injection have yielded a benchmark survival rate of approximately less than 5% several weeks after transplantation,4 whereas this value could be significantly increased by the use of in vitro–engineered tissue constructs.5,6 However, in the study of Mori et al, recipient animals were not treated with immunosuppression, making graft rejection by immune responses a very likely explanation for their finding of lack of long cell retention. The second issue that remains unclear is if ADSCs are indeed an effective cell source for treatment of myocardial injury. Although Mori's study again suggests that paracrine signals can beneficially affect the injured myocardium, like the induction of angiogenesis and suppression of fibrosis, this study also showed that sustained remuscularization is not achieved with ADSCs. In our view, remuscularization with an absolute increase of force-generating cardiomyocytes will be essential to realize long-term restoration of cardiac function.
1. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation
2. Mori D, Miyagawa S, Yajima S, et al. Cell spray transplantation of adipose-derived mesenchymal stem cell recovers ischemic cardiomyopathy in a porcine model. Transplantation
3. Frese L, Dijkman PE, Hoerstrup SP. Adipose tissue-derived stem cells in regenerative medicine. Transfus Med Hemother
4. van der Bogt KEA, Sheikh AY, Schrepfer S, et al. Comparison of different adult stem cell types for treatment of myocardial ischemia. Circulation
5. Riegler J, Tiburcy M, Ebert A, et al. Human engineered heart muscles engraft and survive long term in a rodent myocardial infarction model. Circ Res
6. Weinberger F, Breckwoldt K, Pecha S, et al. Cardiac repair in guinea pigs with human engineered heart tissue from induced pluripotent stem cells. Sci Transl Med