The biology and potential issues related to clinical applications of human mesenchymal stem cells

Abstract

With the advance of biological technology, using different forms of human stem cells for clinical purposes is becoming a reality. However, there are limitations for each type of stem cells in actual clinical applications. That includes legal restriction, ethical concerns, tissue histocompatibility, biological safety, etc. Adult stem cells, such as hematopoietic stem cells and mesenchymal stem cells (MSCs), are less affected by these limitations so they can be used clinically. Human MSCs are adult stem cells that can be differentiated into a wide spectrum of human somatic cell types. Their usage in regenerative medicine such as for bone and cartilage repair is relatively established. But their long-term engraftment status remains undetermined. In addition, human MSCs are the most potent immunosuppressive cells currently known. Promising initial clinical results showed benefit but subsequently large-scale multi-center clinical trials often did not achieve the expected outcome. What may account for this discordance should be thoroughly investigated. My team has been looking at these issues over the last 2 decades and tried to find solution. There are many additional hurdles to overcome including donor availability, quality control of the cells, high throughput production bottleneck, etc. Each of these hurdles has their respective etiology and potential solution. Therefore, the framework of my study were based on specific difficulties encountered with corresponding cause finding and solution searching.

We provided evidence to support that adipose tissue is the better source to yield MSCs and the possible underlying mechanism may involve a complement lysis decay-acceleration factor (CD55). There are different ways to harvest bone marrow derived MSCs and we identified the differences in MSCs yield based on the donors’ condition. In contrary to blood cells, MSCs are adherent cells and detachment will induce anoikic stress and cell death. To counteract anoikic stress, we provided a novel way of using collagen microsphere to facilitate local delivery of MSCs and suggested pre-treatment with chemotactic factor, SDF-1, can minimize anoikic stress and enhance systemic delivery of MSCs. Another important confounding factor affecting the efficacy of MSCs is the hostile extrinsic environments, which can affect survival and function of MSCs. We therefore examined different extrinsic factors such as bacterial endotoxin and viral infection on the proliferation and differentiation of MSCs. Furthermore, inflammatory cytokines and apoptotic cells can also alter the biology and function of MSCs. These studies provide some guidance on the proper application of MSCs to achieve optimal results. To solve the batch-to-batch variation issue, we proposed the use of induced MSCs from induced pluripotent stem cells and this can provide unrestricted number of cell source and overcome the heterogeneity issue of MSCs. We also designed an automated bioreactor using microbeads with a mobile fluidic chamber so we can improve the throughput of MSCs. In summary, we reviewed the current obstacles of clinical application of MSCs. The etiology of several important issue was analyzed, and the underlying biology was studied. Then we designed interventional strategy to overcome each of these issues. These findings contribute to the future wider applications of MSCs clinically.