Stem cells in regenerative medicine
With the beginning of the new millennium, great hopes were placed in the rapidly developing field of stem cell research. It was and is the goal to develop stem cell therapies that help to successfully treat a wide range of degenerative diseases as well as more acute diseases such as stroke or myocardial infarction. Conceptually, it was assumed that injected stem cells or their descendants migrate into affected tissues and replace lost cell types via transdifferentiation, thus alleviating disease associated symptoms. At that time, human embryonic stem cells came into focus of scientific interest. However, due to their high teratogenic potential and ethical explosiveness they could not be used for stem cell therapies. Instead, various somatic stem cell types were considered and used as therapeutic agents.
MSCs
Especially fibroblastoid cells that can easily be raised from bone marrow and other tissues (including fat and umbilical cord) and that were initially described by Friedenstein and colleagues in the 1960s [1], became the therapeutic cell source of choice in a still increasing number of clinical trials. Such cells display high proliferation potential and lack teratogenic potential. Since these cells were able to differentiate into adipogenic, chondrogenic and osteogenic cell types, (which are considered as mesodermal derivatives), they were initially referred to as mesenchymal stem cells (MSCs) [2]. Relying on their therapeutic potential and the fact that their use in animal models produced no recognizable side effects [3], MSCs were then also used successfully in initial therapeutic trials. The question quickly arose as to how the immune system responds to the application of donor MSCs. While it was initially thought that MSCs are rejected in principle, it has been shown that MSCs can modulate the activity of different types of immune cells in patients. They very efficiently suppress immune effector responses and propagate regulatory immune responses, that is, they switch the immune system from the defense to the tolerance state [4-6]. In addition to the regenerative potential of MSCs, their immunotherapeutic activity has been tested in the clinic [7]. To date, nearly 1,000 clinical trials have been registered at the National Institute of Health (NIH) in, which MSCs had been or will be used to treat a wide variety of different diseases (www.Clinicaltrials.gov).
Although the outcome of several clinical studies appears controversial, many studies show therapeutic effects of applied MSCs in at least some patients. Ongoing studies that investigated the bio-distribution of injected or infused MSCs in vivo have shown that most of the cells end up in the lungs and only occasionally are found in the region of the intended target tissue. Attempts to clarify whether the cells need to migrate into affected tissues to achieve their therapeutic functions demonstrated that in most cases MSCs act in a paracrine rather than a cellular manner [8, 9]. The differentiation potential of MSCs, which sometimes was regarded as pluripotent, has also been questioned experimentally. Consequently, today, many scientists question the stem cell character of MSCs. To keep the abbreviation MSC, these cells are now increasingly referred to as mesenchymal stromal cells; also the term medical signaling cells has been suggested by a leading MSC researcher [10].
Whatever MSCs may be called in the future, many scientists have tried to identify the active therapeutic substance(s) that they release into their environment. In 2009, at the example of an acute renal damage model and in 2010, at the example of a myocardial infarction model, and by using different preparation methods, two groups demonstrated that the active component is located in fractions of processed culture supernatant that contain high concentrations of vesicular structures. At that time these vesicles were called microvesicles or exosomes, respectively; today, one would correctly refer to them as extracellular vesicles (EVs) [11, 12].
