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Mesenchymal stem cell therapy in clinic: current status and problems

The very recent review by James Ankrum and Jeffrey Karp: Mesenchymal stem cell therapy: Two steps forward, one step back [1], summarizes the current status of clinical mesenchymal stem cell therapy and analyzes the problems which these trials are facing.

Mesenchymal stem cell (MSC) therapy is poised to establish a new clinical paradigm; however, recent trials have produced mixed results. Unfortunately, although clinical trials have met safety endpoints, efficacy has not been demonstrated. We believe the challenge to demonstrate efficacy can be attributed in part to an incomplete understanding of the fate of MSC following infusion.

I really like this review, because it’s very analytical and up-to-date. I’d like to highlight some very important points made in the review. First of all they did a great job, summarizing all current clinical trials using MSC.


They concluded that there are at least 101 trials total launched and available for analysis (based on submissions to www.ClinicalTrials.gov [2]), including 59 allogeneic MSC transplantation and 42 – autologous; 21 trials were completed at the moment; total number of patients treated – 5344. Countries that contributed most in total number of trials: USA – 31; Europe overall – 22; China – 16. Authors made an excellent detailed table summarizing all of trials. Most frequent indications: bone/cartilage diseases – 26 trials; cardiovascular diseases – 19; GvHD – 16; neurology – 12.

clinical trials start to meet some problems on phase II-III

Safety – phase I of clinical trials usually go smoothly in every indication, but when the trials reach phase II and especially randomized placebo-controlled studies, we start to see more mixed results and failures. For example – Osiris Prochymal trial for GvHD phase III [3].

Although the mixed clinical data could be considered a major setback to the entire MSC field, these trials extended initial phase I safety data to thousands of patients, and we believe this should be considered a critical milestone, particularly given that typical doses include hundreds of millions of allogenic MSC. It is also important to consider that it took several decades to optimize bone marrow transplantation before it became a standard of care.

paradigm shift in understanding of therapeutic efficiency

    – moving focus from the therapies based of MSC differentiation capacity to trials which focused on MSC trophic function (direct differentiation mechanisms versus paracrine, endocrine functions and immunomodulation);
    – very low homing and engraftment rate (below 1%) and entrapment in the lungs favors indirect – trophic mechanisms and immunomodulation function versus differentiation in mesenchymal lineages.

Unlike conventional drugs, which are designed to act through a known pathway, cell therapies are living therapeutics, which can multiply, senesce, undergo necrosis or apoptosis, or alter their phenotype, and thereby drastically change their therapeutic potential.

challenges in basic biology

    – nomenclature (correct name of MSC);
    – characterizing and defining the MSC phenotype (too many different markers proposed – leads to lack of standardization);
    – heterogeneity and comparison populations between tissues and withing one tissue.

future development

    – monitoring of fate and tracking migration of MSC after transplantation;
    – local delivery to specific tissue when there is an indication;
    – better characterization of MSC and cell culture conditions for isolation of therapeutically relevant cells.

ClinicalTrials.gov registry currently lists 101 trials that are using exogenous MSC to treat a wide range of damaged, diseased or inflamed tissues. Because only 21 of these trials have been completed, we can anticipate an abundance of new human data in the near future for a wide range of therapeutic applications (21 trials are scheduled to be completed in 2010 and 20 trials in 2011). Through investigation of MSC biology, discovery of their therapeutic mechanisms within animal models and testing their therapeutic potential within human trials, we will hopefully achieve many more steps forward to make MSC therapy a new clinical paradigm.

Very good review. Highly recommended to read!