Mesenchymal stem cells (MSCs) are one of a few stem cell types to be applied in clinical practice as therapeutic agents for immunomodulation and ischemic tissue repair. In addition to their multipotent differentiation potential, a strong paracrine capacity has been proposed as the principal mechanism that contributes to tissue repair. Apart from cytokine/chemokine secretion, MSCs also display a strong capacity for mitochondrial transfer and microvesicle (exosomes) secretion in response to injury with subsequent promotion of tissue regeneration. These unique properties of MSCs make them an invaluable cell type to repair damaged tissues/organs. Although MSCs offer great promise in the treatment of degenerative diseases and inflammatory disorders, there are still many challenges to overcome prior to their widespread clinical application. Particularly, their in-depth paracrine mechanisms remain a matter for debate and exploration. This review will highlight the discovery of the paracrine mechanism of MSCs, regulation of the paracrine biology of MSCs, important paracrine factors of MSCs in modulation of tissue repair, exosome and mitochondrial transfer for tissue repair, and the future perspective for MSC-based therapy.Key words: Mesenchymal stem cells (MSCs); Mechanism; Paracrine effects effective cell source in cell-based treatment. The fascinating therapeutic effects of MSCs in various life-threatening human diseases, including cerebral spinal cord injury, hematological disorders, cardiovascular diseases, diabetes, immune diseases, graft versus host diseases (GvHDs), and cancer, are well documented. Nonetheless, the indepth mechanisms of how MSCs act remain a matter for debate and exploration. The generally putative concepts cover transdifferentiation, cell fusion, paracrine effects, microvesicles carrying messenger RNA (mRNA) or microRNA (miRNA) and mitochondrial transfer (Fig. 1) (8,9,16,31,34,35,43,97,101,136). This review will focus on the paracrine effects of MSCs, the most comprehensive and enduring mode of action that ascribes to functional recovery in both acute and chronic responses.

Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). Because CS leads to mitochondrial dysfunction, we aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived MSCs (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for 1 hour daily for 56 days. At Days 29 and, human iPSC-MSCs or adult bone marrow-derived MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (P < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (P < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than in the BM-MSC-treated group (P < 0.05). This might have contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs, with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes. Inhibition of tunneling nanotube formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD.

Mesenchymal stem cells (MSCs) are multipotent cells capable of self-renewal and differentiation. There is increasing evidence of the therapeutic value of MSCs in various clinical situations, however, these cells gradually lose their regenerative potential with age, with a concomitant increase in cellular dysfunction. Stem cell aging and replicative exhaustion are considered as hallmarks of aging and functional attrition in organisms. MSCs do not proliferate infinitely but undergo only a limited number of population doublings before becoming senescent. This greatly hinders their clinical application, given that cultures must be expanded to obtain a sufficient number of cells for cellbased therapy. Here, we review the current knowledge of the phenotypic and functional characteristics of senescent MSCs, molecular mechanisms underlying MSCs aging, and strategies to rejuvenate senescent MSCs, which can broaden their range of therapeutic applications.