When talking about regenerative medicine in general, and stem cells in particular, it is necessary to clarify at least some of the aspects of the physiology of these cells. Many lay people automatically think of embryonic stem cells when “stem cell therapy” is mentioned, but in reality at present no clinical application exists for embryonic stem cells.
This is based not only on ethical concerns and the risk of development of certain tumors derived from embryonic stem cells, but also on the fact that these cells are not the patient’s own cells. This may cause transplant rejection reactions, and prevent integration of cells derived from embryonic stem cells into the host tissue. Even for so-called induced pluripotent stem cells (iPS cells) clinical applications are missing, not only for the complexity of the procedure, but particularly based on the risk of the development of cancer by these cells.
To better understand the general idea behind the application of stem cells in regenerative medicine, one should realize that, under physiological conditions, maintenance and restoration of organ function is mostly achieved by local cells, including so-called tissue resident stem cells. However, in the event of acute trauma or disease, the sudden demand of new cells during the healing response may exceed the plasticity of the local cell populations. Furthermore, the ability of the tissue resident stem cells to re-enter the cell cycle and to asymmetrically divide is limited: this eventually limits the extent of self-renewal (and, thus, the self-healing power of the body) following major loss of cells in damaged tissue.
However, there is a further type of stem cells present in the adult body, with the potential to develop (differentiate) into cells of all three embryonic germ layers (ectoderm, mesoderm, endoderm). These cells, which are termed vascular associated pluripotent stem cells (vaPS cells), are located in the walls of small blood vessels. Since blood vessels are the basis for the formation of tissue and organs in a developing body, these vaPS cells are also found in every organ of the adult body. It is currently unknown to which extent these vaPS cells participate in the physiological maintenance and restoration of organ functions. In any case, unlike embryonic stem cells and iPS cells, vaPS cells do not have their own, intrinsic program for the formation of new tissue, but become active in response to specific signals released and transmitted by diseased tissue. Considering this fundamental difference, the vaPS cells have become an attractive option for regenerative therapy purposes without the risk of malignant transformation.
As long as the aforementioned local self-healing power of the body is sufficient to restore physiological body structures and functions in the event of trauma or disease, all treatment efforts should primarily focus on this. A variety of methods, including but not limited to physiotherapy, osteopathy, extracorporeal shock wave therapy (ESWT), laser therapy and the injection of platelet-rich plasma (PRP), can make valuable contributions through stimulation of local regeneration.
However, a patient’s body’s localized self-healing power can eventually exhaust. As a consequence, physiological body structures and functions can no longer be restored by the local stem cell pool. If this happens in the musculoskeletal system, further conservative measures will have a high risk of failure. In essence, one can treat the patient with as much physiotherapy, ESWT, laser or other modalities as desired, and one can inject as much PRP as one wishes and patients request: these interventions will not work, or they only work to a limited extent because the cells that are supposed to effect the repair are simply not there any longer, or cannot adequately react to stimulation.
This is exactly where the targeted use of the body’s own vaPS cells comes into play, because they can be harvested and isolated from the body’s own adipose tissue. Practically every one of us has a certain amount of body fat, which the organism can spare, and which can be obtained by mini-liposuction on the abdomen, the flanks or the thighs in an outpatient procedure with low risk and without general anesthesia; 100 grams of adipose tissue are sufficient in most instances. Adipose derived regenerative cells (ADRCs) (which contain the vaPS cells]) can then be isolated from the adipose tissue using relatively simple technologies. ADRCs are a mixture of cells including vaPS cells, progenitor cells, cells of the walls of the blood vessels (pericytes, endothelial cells, endothelial precursor cells and fibroblasts) and blood cells. Until a few years ago, it was thought that it was important to isolate the stem cells from the ADRCs in the next step and to multiply them in the laboratory (i.e. in cell culture) before using them therapeutically, resulting in so-called adipose derived stem cells (ADSCs). However, there is now good evidence that uncultured ADRCs are superior to cultured ADSCs for regeneration of tendons and bone. One of the reasons for this is that uncultured ADRCs contain cell types that can no longer be found in cultured ADSCs.
The use of fresh, uncultured ADRCs instead of cultured ADSCs has two other important advantages for the patient: (i) as the cells are not cultivated in a laboratory, the possible risk of contamination by bacteria and viruses is avoided, and (ii) treatment with uncultured ADRCs is a real point of care procedure. Within a very short time span and in the same surgical setting, the adipose tissue can be obtained by mini-liposuction and the ADRCs can be injected to the point in the body where they are needed.
As evidenced by a large number of animal studies, treatment of pathologies of the musculoskeletal system with ADRCs is safe (i.e. does not lead to the development of cancer and other undesirable side effects) and treatment with ADRCs or ADSCs leads to a significant improvement of the structure and function of a damaged organ or tissue. Based on these highly positive results, treatment of human patients specifically with uncultured ADRCs started a few years ago. Both of us have been involved in a feasibility study approved by the U.S. Food and Drug Administration (FDA), that demonstrated for the first time that in patients suffering from symptomatic, partial-thickness rotator cuff tear (sPTRCT) who had not responded to over six weeks of conservative management, a single application of ADRCs led to rapid and long-lasting improvement in the clinical situation, with an improvement in the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) total score from 58.7 ± 19.2 (mean ± standard error of the mean) before treatment to 86.1 ± 4.9 at 24 weeks post treatment and 89.4 ± 4.9 one year post treatment (Hurd et al., J Orthop Surg Res 2020;15(1):122). The results of a control group of patients treated with corticosteroid injections (a standard therapy for the condition at hand) were statistically significantly worse than the results of the patients treated with ADRCs (in the control group the mean ASES score was 50.6 ± 6.7 before treatment, 60.8 ± 6.2 at 24 weeks post treatment and 68.4 ± 4.4 one year post treatment). In retrospect, the poor performance of the standard therapy (injection of corticosteroid) is not really surprising when it becomes clear that, when the local self-healing power of the body is exhausted, the injection of corticosteroids certainly leads to reduction of inflammation (and thus pain relief) in the affected shoulder, but cannot result in healing. To verify the results of this initial safety and feasibility pilot study in a larger patient population, a randomized controlled trial on 246 patients suffering from sPTRCT is currently ongoing.
Of note, no special follow-up treatment is necessary after the application of ADRCs. Accordingly, patients can return to routine care immediately after the application of ADRCs.
Summary
In summary, the use of ADRCs in the management of pathologies of the musculoskeletal system (including tendons) seamlessly fits into modern orthopedic treatment concepts. The patients receive treatment with their own body’s self-healing power, which is just recovered and transferred from one “healthy” site to another site of the body in need for repair. This reflects a natural and intrinsically existing mechanism of the body, to mobilize stem cells from adipose tissue (however, in often not sufficient amounts) and transfer cells for “self-healing” to damaged organs and tissues in need for repair.
Autoren
ist Inhaber des Lehrstuhls II der Anatomischen Anstalt der Ludwig-Maximilians Universität München und wissenschaftlicher Beirat der sportärztezeitung.
ist einer der weltweit führenden klinischen und akademischen Experten für Sehnenpathologien und -regeneration, mit akademischen Berufungen und Anstellungen in Italien (Universität Salerno) und GB (Queen Mary University of London, London, England; Keele University School of Medicine, Stoke-on-Trent, England).
