Sfrp1 as a Pivotal Paracrine Factor in the Trained Pericardial Stem Cells that Foster Reparative Activity

Tissue damage often induces local inflammation that in turn dictates a series of subsequential responses, such as stem cell activation and growth, to maintain tissue homeostasis. The aim of the study is to testify the possibility of using inflammation-trained stem cells as optimal donor cells to augment the efficacy of cell therapy. The pericardial stem/stromal cells derived from the animals after myocardial infarction (MI-pSC) showed an enhanced myogenic potential and augmented reparative activity after transplantation in the injured hearts, as compared to the Sham-pSC. Bulk RNA-Seq analysis revealed significant upregulation of a panel of myogenic and trophic genes in the MI-pSC and, notably, Sfrp1 as an important anti-apoptotic factor induced robustly in the MI-pSC. Injection of the MI-pSC yielded measurable numbers of surviving cardiomyocytes (Tunel and Casp-3 negative) within the infarct area, but the effects were significantly diminished by siRNA-based silence of Sfrp1 gene in the pSC. Primed Sham-pSC with pericardial fluid from MI rats mimicked the upregulation of Sfrp1 and enhanced myogenic potential and reparative activity of pSC. Taken together, our results illustrated the inflammation-trained pSC favor a reparative activity through upregulation of Sfrp1 gene that confers anti-apoptotic activity in the injured cardiomyocytes. Therefore, the active form of stem cells may be used as a cardiac protective agent to boost therapeutical potential of stem cells.