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The Touchy-Feely Side of Cardiac Cell Therapy

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Review of “Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells” from Stem Cells by Stuart P. Atkinson

The innate renewal ability of the human heart is not sufficient to remedy the huge loss of cardiomyocytes following myocardial infarction (MI), but methods which boost cardiomyocyte renewal may have some therapeutic value. Cardiosphere‐derived cells (CDCs) have the ability to induce cardiomyocyte cell cycling in animal models [1, 2] and this may also extend to humans [3]. Many attribute classic paracrine action as the main mechanism behind this induction; effects are observed up to 6 months after transplantation although cells are not retained in the heart past 4 weeks [4]. However, physical contact of CDCs with cardiomyocytes may initiate a cascade effect within the cells, and may represent another important mechanism. Researchers from the laboratories of Eduardo Marbán (Cedars-Sinai Heart Institute, Los Angeles, California, USA) and Yucai Xie (Shanghai Jiao Tong University School of Medicine, China) have begun to investigate this mechanism, and have found that cell-to-cell contact is vitally important for cardiomyocyte proliferation [5].

Initial studies found that co-culture of neonatal rat cardiomyocytes with CDCs significantly boosted the number of proliferating cells as a function of time. This required cell contact for the optimal effect, as when the researchers co-cultured cells in transwell culture inserts to share medium but keep the cells physically apart, the percentage of proliferating cells dropped. Immunohistochemical assessment of hearts after injection of CDCs, CDC conditioned medium (CDC-CM) or vehicle into SCID mouse hearts after MI confirmed this finding. CDC injections led to the greatest number of cycling cardiomyocytes in the MI border zone, even though CDC-CM had a pronounced effect also (See Figure). Whilst the vehicle group deteriorated, CDC injection led to the preservation of cardiac function, and the functional benefit from CDC-CM injection was minimal and insignificant.

In an attempt to understand how cell contact mediates this effect, the researchers blocked Integrin signalling, known to mediate adhesion, signal transduction and cell cycle regulation [6], with special attention paid to β1 integrin due to its roles in myocardial growth and development [7]. Blocking β1 integrin with an antibody mediated a reduction in the number of proliferating cardiomyocytes in CDC co-culture, although this did not occur when cardiomyocytes were grown with CDC-CM. β1 integrin integrates with growth factors through various other signalling pathways, and use of specific inhibitors allowed the researchers to define the MEK and PI3K pathways as important to cell contact-mediated cardiomyocyte proliferation. Lastly, using antibody blocking and both in vitro and in vivo experiments, the researchers demonstrated that intact β1 integrin on cardiomyocytes, and not on CDCs, is required for the induction of proliferation.

This study highlights the fact that, while most studies presume that the fleeting presence of cells at sites of interest means a paracrine effect of therapeutic cells only, cell-to-cell contact is also important for therapeutic benefit. Furthermore, they identify mechanisms by which cell-to-cell contact may mediate its long term effects. The authors however do note some limitations to their study which require further research. These include the possibility of cardiac progenitor recruitment, protein stability problems in comparing the role of CDCs and CDC-CMs, and finally the identification of CDC ligands which activate β1 integrin signaling in cardiomyocytes.

Discussion

  • Is this finding relevant to other fields, such as neural cell transplantation?
  • Are key pathways conserved or cell type specific?
  • Can we mimic cell-to-cell contact through pathway modulation and improve cell transplant success?

References

  1. Cheng K, Shen D, Smith J, et al. Transplantation of platelet gel spiked with cardiosphere-derived cells boosts structural and functional benefits relative to gel transplantation alone in rats with myocardial infarction. Biomaterials 2012;33:2872-2879.
  2. Malliaras K, Li TS, Luthringer D, et al. Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells. Circulation 2012;125:100-112.
  3. Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 2012;379:895-904.
  4. Liu J, Narsinh KH, Lan F, et al. Early stem cell engraftment predicts late cardiac functional recovery: preclinical insights from molecular imaging. Circ Cardiovasc Imaging 2012;5:481-490.
  5. Xie Y, Ibrahim A, Cheng K, et al. Importance of cell-cell contact in the therapeutic benefits of cardiosphere-derived cells. Stem Cells 2014;
  6. Streuli CH and Akhtar N Signal co-operation between integrins and other receptor systems. Biochem J 2009;418:491-506.
  7. Ieda M, Tsuchihashi T, Ivey KN, et al. Cardiac fibroblasts regulate myocardial proliferation through beta1 integrin signaling. Dev Cell 2009;16:233-244.