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Placental Stem Cells Aid Cardiac Repair

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Review of “Human Placenta-Derived Adherent Cells Improve Cardiac Performance in Mice with Chronic Heart Failure” from Stem Cells TM by Stuart P. Atkinson

Stem cell therapy is an emerging strategy for the treatment of heart failure, the leading cause of worldwide morbidity and mortality [1]. Bone marrow stem cell transplantation had initially demonstrated some success in cardiac repair after myocardial infarction (MI) [2], although more recent studies have not confirmed this finding. Now scientists from the groups of Patrick C.H. Hsieh (Institute of Biomedical Sciences, Taiwan) and Uri Herzberg (Celgene Cellular Therapeutics, New Jersey, USA) have assessed human placenta-derived adherent cells (hPDACs) as a possible means to promote cardiac repair. hPDACs are similar to mesenchymal stem cells and display immunomodulatory, anti-inflammatory, pro-regenerative, angiogenic, and neuroprotective properties [3-6]. The results, published in Stem Cells Translational Medicine demonstrate that intramyocardial (IM) injection of hPDACs has the ability to improve cardiac performance and reduce fibrosis in a mouse model of chronic heart failure (CHF) [7].

The researchers utilized an intravenous formulation of PDAC (PDA-001 (cenplacel-L)) which is in clinical development for the treatment of autoimmune and inflammatory diseases [8]. Using trans-aortic constriction as a model of CHF, the authors first compared the effects of intravenous (IV) and IM injections of PDA-001 on left ventricular ejection fraction (LVEF). While IV injection brought not obvious improvements, IM injection led to increased regional myocardial contractions, but did not prevent global ventricular dilatation (see figure). IM injection also reduced cardiac fibrosis, increased capillary density at the injected site, and reduced C-reactive protein (CRP) levels suggesting a modest anti-inflammatory effect.

How exactly does PDA-001 effect these changes? The authors found IM injection led to increased endothelial cell and cardiomyocyte proliferation at the injection sites, although cell tracking studies found that injected cells had a low persistence in the heart and so may promote their effects through paracrine action.

While this research is encouraging, moving this research forward will require further optimization of the cells dosing, timing of injection, and cell delivery. Low doses of PDACs (50,000) seems to be as effective as higher doses, but a more effective means to cover the left ventricle fully and for an increased duration (e.g. absorbable bioscaffolds) may improve cardiac function further. The current strategy administered cells at 3 weeks after trans-aortic constriction, and while this did have an obvious effect, injection nearer to the time of MI may enhance the effect of PDACs if they are primarily acting by dampening inflammation and mediating cell recovery through excreted factors.

References

  1. Jessup M and Brozena S Heart failure. The New England journal of medicine 2003;348:2007-2018.
  2. Jeevanantham V, Butler M, Saad A, et al. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation 2012;126:551-568.
  3. Chen J, Shehadah A, Pal A, et al. Neuroprotective effect of human placenta-derived cell treatment of stroke in rats. Cell transplantation 2013;22:871-879.
  4. He S, Khan J, Gleason J, et al. Placenta-derived adherent cells attenuate hyperalgesia and neuroinflammatory response associated with perineural inflammation in rats. Brain Behav Immun 2013;27:185-192.
  5. Li X, Ling W, Pennisi A, et al. Human placenta-derived adherent cells prevent bone loss, stimulate bone formation, and suppress growth of multiple myeloma in bone. Stem Cells 2011;29:263-273.
  6. Liu W, Morschauser A, Zhang X, et al. Human placenta-derived adherent cells induce tolerogenic immune responses. Clin Transl Immunology 2014;3:e14.
  7. Chen HJ, Chen CH, Chang MY, et al. Human placenta-derived adherent cells improve cardiac performance in mice with chronic heart failure. Stem Cells Translational Medicine 2015;4:269-275.
  8. Mayer L, Pandak WM, Melmed GY, et al. Safety and tolerability of human placenta-derived cells (PDA001) in treatment-resistant crohn's disease: a phase 1 study. Inflamm Bowel Dis 2013;19:754-760.