Fight Aging!

We are something like thirty years into the increasingly widespread use of first generation stem cell therapies. Cells are derived from a variety of sources, processed, and transplanted into patients. Near all of these transplanted cells die, but while they survive they secrete signals that suppress inflammation and encourage native cells to change their behavior for the better. It is fair to argue that these treatments have not yet realized the potential originally hoped for, the robust regeneration of damaged tissues. While suppression of inflammation is reliably achieved, regeneration and restored function for organs occurs in only some patients, and to a varying, modest degree.

More generally, not enough is known of how these therapies produce beneficial effects, or of the way in which cells interact in these circumstances. That leads to discussions such as the one offered in today's open access paper, in which clinicians look over their data to make the empirical observation that some sources of cells are better than others for treating specific conditions. Why this might be the case, or even whether it would still be the case in broader datasets, is an open question. Too little is known, much more research is needed, and this is the case decades into the development of this field!

If the original vision for cell therapies is to be realized, then the future of this field must be one in which the challenges of cell survival and cell integration into tissues are solved, allowing the wholesale replacement of damaged and dysfunctional stem cell populations. This may require the rejuvenation of tissues that make up stem cell niches, as at least some of the evidence accumulated to date suggests that stem cell populations can be functional, even in later life, if only protected from age-related changes in the signaling environment provided by the niche and surrounding tissues. That is a somewhat harder problem to solve than issues involving the transplanted cells themselves. But at the end of the day, defeating the challenges of stem cell therapies may require defeating the challenges of degenerative aging.

Stem cell-based therapy for human diseases

From a cellular and molecular perspective and from our own experience in a clinical trial setting, adipose-derived mesenchymal stem cells (AD-MSCs), bone marrow-derived MSCs (BM-MSCs) and umbilical cord derived MSCs (UC-MSCs) exhibit different functional activities and treatment effectiveness across a wide range of human diseases. In this paper, we have provided up-to-date data from the most recently published clinical trials conducted in neuronal diseases, endocrine and reproductive disorders, skin regeneration, pulmonary dysplasia, and cardiovascular diseases. The implications of the results and discussions presented in this review and in a very large body of comprehensive and excellent reviews as well as systematic analyses in the literature provide a different aspect and perspective on the use of MSCs from different sources in the treatment of human diseases.

We strongly believe that the field of regenerative medicine and MSC-based therapy will benefit from active discussion, which in turn will significantly advance our knowledge of MSCs. Based on the proposed mechanisms presented in this review, we suggest several key mechanistic issues and questions that need to be addressed in the future:

1. The confirmation and demonstration of the mechanism of action prove that tissue origin plays a significant role in the downstream applications of the originated MSCs.

2. Is it required that MSCs derived from particular cell sources need to have certain functionalities that are unique to or superior in the original tissue sources?

3. As mechanisms may rely on the secretion of factors from MSCs, it is important to identify the specific stimuli from the wound environments to understand how MSCs from different sources can exhibit similar functions in the same disease and whether or not MSCs derived from a particular source have stronger effects than their counterparts derived from other tissue sources.

4. Should we create "universal" MSCs that could be functionally equal in the treatment of all diseases regardless of their origin by modeling their genetic materials?

5. Can new sources of MSCs from either perinatal or adult tissues better stimulate the innate mechanisms of specific cell types in our body, providing a better tool for MSC-based treatment?

6. A potential 'priming' protocol that allows priming, activating, and switching the potency of MSCs from one source to another with a more appropriate clinical phenotype to treat certain diseases. This idea is potentially relevant to our suggestion that each MSC type could be more beneficial in downstream applications, and the development of such a "priming" protocol would allow us to expand the bioavailability of specific MSC types.

From our clinical perspective, the underlying proposal in our review is to no longer use MSCs for applications while disregarding their sources but rather to match the MSC tissue source to the application, shifting from one cell type for the treatment of all diseases to cell source-specific disease treatments. Whether the application of MSCs from different sources still shows their effectiveness to a certain extent in the treatment of diseases or not, the transplantation of MSCs derived from different sources for each particular disease needs to be further investigated, and protocols need to be established via multicentre, randomized, placebo-controlled phase II and III clinical trials.