**7. Conclusions**

Accumulative evidence has shown that the adaptive immune response is involved in post-ischemic cardiac remodeling after MI. From the acute to chronic phase, T cells have played an important role in the mediation of tissue repair following cardiac injury. Tregs can terminate the pro-inflammatory phase and initiate the anti-inflammatory or regenerative phase, promoting the di fferentiation of Ly6Chigh monocytes toward M2 macrophages in the myocardium by secreting pre reparative cytokines including IL-10, IL-13, and TGF-β. They also stimulate fibroblasts directly in the myocardium. Paracrine signaling to and from immune cells and stem cells can be key in understanding the wound healing process after cardiac injury. Stem cells can induce Tregs via direct and indirect mechanisms. However, the mechanism behind polarization of di fferent T cell subsets after stem cells transplantation remains poorly understood. If we focus on the UPS and its e ffect on cell therapy, it can give us some clues on how to modulate a pro-reparative phenotype especially associated with Tregs. This may potentially unravel some mechanisms that can augmen<sup>t</sup> cardiac healing after ischemic injury. The development of new therapeutic strategies targeting the adaptive immune system in IHD and via stem cells and its interplay with the UPS can contribute to be a more e ffective treatment in patients with heart disease.

**Author Contributions:** T.K. performed collection of references and wrote the current manuscript. M.K. and S.M. supervised review scope and aided in the preparation of the current manuscript. All authors have read and agreed to the published version of the manuscript.

**Funding:** The work was supported by National Institute of Health gran<sup>t</sup> HL137850 and American Heart association gran<sup>t</sup> 15SDG25550038 to S.M. and NIH HL135177, AHA Scientific Development Grant 15SDG22680018 and H1801 WW Smith Charitable Trust to M.K.

**Acknowledgments:** We thank all Mohsin Lab members for their input.

**Conflicts of Interest:** The authors declare no conflict of interest.
