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Predicting Cardiac Progenitor Cell Therapy Outcomes in the Failing Heart with miRNA Profiles

Review of “Predicting Functional Responses of Progenitor Cell Exosome Potential with Computational Modeling” from STEM CELLS Translational Medicine by Stuart P. Atkinson

A recent study from the laboratory of Michael E. Davis (Emory University School of Medicine, Atlanta, Georgia, USA) discovered that aggregating cardiac progenitor cells (CPCs) into three dimensional (3D) spheres improved their ability to treat heart failure, with exosomes a significantly contributing factor [1]. In additional studies, the team also established that hypoxic treatment altered exosome content, which included micro(mi)RNAs [2], and used a systems biology approach using statistical tools to model variations in exosome cargo and predict functional outcomes from exosome therapy [2-4].

Now, the team returns with a new STEM CELLS Translational Medicine study that employs a data‐driven computational modeling technique to establish a mathematical relationship between exosomal miRNA and biological responses in a rat myocardial infarction model. Trac et al. hope that their new research findings will highlight those miRNAs critical for biological responses in the hope of bridging gaps between in vitro and animal/human studies [5].

Initial comparisons of exosomes derived two dimensional (2D) monolayer CPC cultures or 3D spheres established that treatment with 3D-CPC exosomes significantly enhanced in vitro angiogenesis and reduced fibrosis-related gene expression. The authors then compared the miRNA content of 2D- and 3D-CPC exosomes and asked whether specific patterns of expression related to therapeutic responses using a computational modeling approach known as partial least squares regression (PLSR). PLSR finds linear relationships within variables and matches them to outputs, which the user can then associate with biological information. Fascinatingly, PLSR analysis provided a list of just 40 miRNAs linked to in vitro biological responses whose targets fit well with cardiac angiogenesis and fibrosis pathways. 

A previous study from the Davis laboratory established that 3D CPCs improved right ventricular vessel density in a rat myocardial infarction model in a Notch‐dependent manner [1]; however, they failed to explore the effect of Notch1 inhibition on 3D-CPC exosome‐mediated angiogenic function. To determine if their PLSR model could predict angiogenic function in this case, the authors measured levels of miRNAs in CPCs from this study and predicted a reduced level of angiogenesis in response to 3D-CPCs treated with a Notch inhibitor. Fascinatingly, in vitro angiogenesis assays confirmed this response, and one of the primary miRNAs predicting therapeutic outcomes (miR‐423‐5p) displaying decreased expression.

Additionally, the authors used their in vitro-trained PLSR model to “predict” the in vivo therapeutic outcomes observed in their previously published studies that demonstrated how younger CPC exosomes had a greater ability to repair the heart after myocardial infarction [1] and how hypoxic treatment enhanced this effect [2]. Encouragingly, following the input of miRNA expression profiles, the predicted therapeutic outcomes from the model correlated well with observed responses following the treatment of model mice and could have accurately predicted responses before animal experiments [2].

Overall, the authors believe that the robust prediction of in vivo exosome function from in vitro analyses represents a step toward producing patient‐specific exosome therapeutics by identifying optimal donors and stem cell manipulations to produce maximally functional exosome therapies.

For more on how computational modeling, cardiac progenitor cells, and exosomes combine to facilitate the treatment of heart failure, stay tuned to the Stem Cells Portal!

 

References

  1. Trac D, Maxwell Joshua T, Brown Milton E, et al., Aggregation of Child Cardiac Progenitor Cells Into Spheres Activates Notch Signaling and Improves Treatment of Right Ventricular Heart Failure. Circulation Research 2019;124:526-538.
  2. Agarwal U, George A, Bhutani S, et al., Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients. Circulation Research 2017;120:701-712.
  3. Agarwal U, Smith AW, French KM, et al., Age-Dependent Effect of Pediatric Cardiac Progenitor Cells After Juvenile Heart Failure. STEM CELLS Translational Medicine 2016;5:883-892.
  4. Gray Warren D, French Kristin M, Ghosh-Choudhary S, et al., Identification of Therapeutic Covariant MicroRNA Clusters in Hypoxia-Treated Cardiac Progenitor Cell Exosomes Using Systems Biology. Circulation Research 2015;116:255-263.
  5. Trac D, Hoffman JR, Bheri S, et al., Predicting Functional Responses of Progenitor Cell Exosome Potential with Computational Modeling. STEM CELLS Translational Medicine 2019;8:1212-1221.