How to Make the Mesenchymal Stem Cells Therapy More Targeted, More Accurate, and More Efficient?

To the Editor: We read the article, with great interest, by Brock et al entitled ‘‘Osseous flap of galea and periosteum filled with mesenchymal stem cells, platelet-rich plasma, bone dust, and hyaluronic acid’’ in J Craniofac Surg. In this article, Brock et al reported that the application of mesenchymal stem cells (MSCs) could improve the quality and bone tissue organization. We consider that there are some practical problems to be solved for proper application which would advance the rational design of nextgeneration MSCs-based therapeutics. Over the years, our understanding of the nature and function of MSCs has undergone a number of paradigm shifts. Initially MSCbased therapies were anticipated to augment the structure and function of damaged or diseased tissues via the effects of cell replacement. However, it soon became apparent that relatively few MSCs engrafted at these sites of damaged or diseased tissue and the studies in rodents and dogs confirmed that intravenously infused MSCs are caught in the capillaries of the lung and most MSCs are largely cleared. It had been long-known that MSCs could secrete bio-active cytokines and abundant growth factors, which could modulate the immune system, limit inflammation, and aid the healing. So, we adopted the revisionist viewpoint that MSCs affect tissue repair largely via their the paracrine or autocrine effects and MSCs trigger and activate the host’s healing potential. In a word, the repairing function of MSCs due to the ‘‘bystander effect’’ or cell-to-cell communication or exosomes and/or some metabolites and cytokines from MSCs. MSCs have the characteristics of migrating and homing to tumor tissues and MSCs can be readily transduced by a variety of vectors such as adenovirus, lentivirus, and adeno-associated virus. Owing to their relative immune-privilege/-evasiveness and general immune dampening activities, MSCs could be used in an allogenic transplantation and MSCs are therefore well suited as an off-theshelf cell therapeutic agent. Based on the above, MSCs which were transfected anticancer genes are believed to be a potential vehicle in cancer treatment. We agree with the conclusions drawn from Brock. But there are some issues about MSCs that are still in debate and further studies are needed to clarify. We will share our ideas and provide the potential solutions on this topic. The first question in this paper is ‘‘what is the mechanism of the action of MSCs? ’’ Cell replacement or ‘‘bystander effect’’? and How to confirm that? The second question is: How to choose the transplanting path? Which is better? Local or systemic? Intravenous or arterial injection? We agree with the Brock’s conclusions, at the same time we are very interested in Brock’s research. We hope that more detailed mechanism of action and how to choose the optimal transplanting pathway of MSCs could be offered. We will provide 2 solutions to ensure stem cell therapy is more efficient, more practical, and more feasible. The first approach is by coating of MSCs with antibodies or peptides, modifying the surface molecules into endothelium binding molecules, modifying cellular surface molecules, and then coating the cells with specific antibodies, which make the MSCs therapy more targeted, more accurate, and more efficient. The second solution is cell-free treatment. There are several advantages by using of the MSC-derived exosomes or(and) the growth factors or bio-active cytokines extracting from MSCs culture medium. The cell-free treatment avoids the potential threat of cell transfection. And the vesicles of MSCs are small which circulate readily whereas MSCs are too large to circulate easily through capillaries and many MSCs cannot get beyond the first pass capillary bed and the dose of infused MSCs quickly diminishes post-transplantion, and it may be that the delivery of MSCs derived from vesicles can achieve a higher dose that circulates to a greater extent than the larger cells. Therefore, careful attention to detail in targeted MSCs and cell-free treatment may provide a new therapeutic paradigm for MSC-based therapies. Simultaneously, we found multichannel transplantation can further improve the therapeutic effects. The security issues of MSCs in clinical application have been concerned by both doctors and patients. If the MSCs were used improperly, they might result in some side effects, even get a tumor or cancer. Irregular MSCs therapy contains potential danger. Safety issues need to be further confirmed by basic research and large sample data, if the safety and effectiveness issues of MSCs therapy for patients can be guaranteed, MSCs therapy would be the ‘‘golden seed cells’’ for patients, that would benefit the majority of the patients who need MSCs therapy.