Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders

Abstract

Mesenchymal stem cell (MSC) transplantation represents the next breakthrough in the treatment of currently intractable and devastating neonatal disorders with complex multifactorial etiologies, including bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and intraventricular hemorrhage. Absent engraftment and direct differentiation of transplanted MSCs, and the "hit-and-run" therapeutic effects of these MSCs suggest that their pleiotropic protection might be attributable to paracrine activity via the secretion of various biologic factors rather than to regenerative activity. The transplanted MSCs, therefore, exert their therapeutic effects not by acting as "stem cells," but rather by acting as "paracrine factors factory." The MSCs sense the microenvironment of the injury site and secrete various paracrine factors that serve several reparative functions, including antiapoptotic, anti-inflammatory, antioxidative, antifibrotic, and/or antibacterial effects in response to environmental cues to enhance regeneration of the damaged tissue. Therefore, the therapeutic efficacy of MSCs might be dependent on their paracrine potency. In this review, we focus on recent investigations that elucidate the specifically regulated paracrine mechanisms of MSCs by injury type and discuss potential strategies to enhance paracrine potency, and thus therapeutic efficacy, of transplanted MSCs, including determining the appropriate source and preconditioning strategy for MSCs and the route and timing of their administration.

Role of Mesenchymal Stromal Cells as Therapeutic Agents: Potential Mechanisms of Action and Implications in Their Clinical Use

“…MSCs are also capable of providing beneficial effects such as cell survival and proliferation, and to modulate the immune response through paracrine signaling. This paracrine activity includes the secretion of small molecules as growth factors, cytokines, chemokines, and the release of EVs that contain a wide range of molecules such as mensenger RNA, peptides/proteins, and microRNAs [73].…”

“…Together, these secreted factors may inhibit inflammatory responses, trigger angiogenic process, promote endothelial and fibroblast activities, and facilitate the proliferation and differentiation of progenitor cells into tissues in situ [49] (Figure 4). and the release of EVs that contain a wide range of molecules such as mensenger RNA, peptides/proteins, and microRNAs [73].…”

“…Despite the fact that the homeostatic and immunomodulatory activity of MSCs were thought to be reliant on MSC cell number, it has been seen that it depends more on the paracrine factors these cells secrete, also known as ''secretome'', which is produced once MSCs are activated [49,53]. Therefore, in response to environmental cues of the injury site, MSCs are activated and secrete various cytoprotective paracrine factors to enhance regeneration of the damaged tissue [73].…”

Preconditioning strategies for improving the survival rate and paracrine ability of mesenchymal stem cells in acute kidney injury

“…Different donors, sources, route timing and doses of transplanted MSCs may need different preconditioning strategies. The advantages and disadvantages of different preconditioning strategies mentioned in this article are listed in Table . A better understanding of the molecular and cellular mechanisms underlying the preconditioning strategy may help considerably to expand its application in AKI and avoid potential side effect.…”

Cryopreserved H2 O2 -preconditioned human adipose-derived stem cells exhibit fast post-thaw recovery and enhanced bioactivity against oxidative stress

“…We consider that the best strategy is cell in vitro preconditioning before cryopreservation to increase the intrinsic biological activity of ASCs (Baldari et al, ; Boregowda & Phinney, ; Guess et al, ; Oses et al, ), increase stem cell potency, and enhance the regenerative effects of ASC‐based therapies (Amiri, Jahanian‐Najafabadi, & Roudkenar, ). The goal of preconditioning is to induce a beneficial adaptive response in cells, during the stage of in vitro expansion, by exposing them to low levels of a specific stimulus: cytokines, drugs, or various types of stress such as hypoxia, heat shock, nutrient deprivation, acidosis, and/or oxidation (Baldari et al, ; Ezquer, Ezquer, Vicencio, & Calligaris, ; Oses et al, ; Park, Ahn, Sung, Ahn, & Chang, ). It endows cells with the ability to respond effectively to a higher level of the same stimulus.…”