Mesenchymal stem cells (MSCs) have been widely studied and increasingly recognized as a potential therapeutic with the ability to initiate and support tissue regeneration and remodeling. While over 1100 clinical trials have been conducted to assess the therapeutic benefits of MSCs, there continues to be widespread variation surrounding the potential treatment outcomes associated with these cells. 

This review, authored by Chang, Yan, Yao, Zhang, Li, and Mao, focuses primarily on profiling the effects of the secretome, or the effects of paracrine signals of MSC, as well as highlights the various engineering approaches used to improve these MSC secretomes. Chang et al. also review recent advances in biomaterials-based therapeutic strategies for the delivery of MSCs and MSC-derived secretomes.

Recent research has demonstrated paracrine signaling as the primary mechanism of MSC therapeutic efficacy. This shift towards the MSC secretome in applications ranging from cartilage regeneration to cardiovascular and other microenvironments has demonstrated its therapeutic potential in prevalent injury models. Additionally, the versatility of MSCs allows them to be specifically tailored using biomaterials toward specific therapeutic outcomes.

A specific example of MSC secretome’s therapeutic potential is their ability to support cardiovascular tissue repair through minimization of fibrotic scarring of cardiac tissue typically observed to occur during a myocardial infarction (MI). Additionally, research has demonstrated MSC secretomes facilitate the proliferative, angiogenic, and anti-inflammatory phases of the wound healing process.

Secretome transfer occurring between MSCs and other cells in the target area primarily occurs through the release of extracellular vesicles (EVs) and is considered a safer form of therapeutic application compared to MSC therapy.  MSC secretomes can also be specifically engineered through hypoxia, treatment with bioactive agents, and modulating cell-cell and ECM interactions in the MSC culture.

One of the biggest challenges facing the therapeutic efficacy of MSC is their limited cell survival, retention, and engraftment following injection or transplantation (found to be as low as 1% surviving one day after implantation). Recent studies have demonstrated MSC secretome, and specifically, EVs, although they remain a significant obstacle, are a promising alternative and able to bypass a number of cellular challenges, including cell survival.

Further consideration and approaches to increasing survival rates of MSCs include experimenting with a wide variety of biomaterials as a way to promote adaptation in the target implantation area. This includes looking for biomaterials to regulate oxygen tension levels, glucose supply, mechanical stress, and pH levels, which collectively can be used to regulate metabolic pathways of the MSC, effectively influencing cell survival and their ability to be used as therapeutic treatment options.

Despite the recent advances in the use of MSC secretomes and their delivery strategies, Chang et al. call for continued study of the subject and specifically recommend developing a specific set of paracrine cues to be used as a well-defined formulation in future therapeutic applications.  

The authors also point out that the use of EVs and other direct applications of the MSC secretome are thought to be promising for the treatment of osteoarthritis, ischemic stroke, and coronavirus-related diseases. Considering this, Chang et al. highlight the increasing need to fully understand the paracrine signaling effects of MSC therapies and the delivery strategies associated with this application.

Source:  “Effects of Mesenchymal Stem Cell‐Derived Paracrine Signals and ….” 12 Jan. 2021, https://onlinelibrary.wiley.com/doi/full/10.1002/adhm.202001689.

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