In the July 2016 edition of the journal Stem Cells Translational Medicine, a report has been published that lays out the results of a phase I clinical trial that used mesenchymal stem cells from a patient’s own fat tissues to treat osteoarthritis of the knee. This study was not placebo controlled, but did examine the effects of escalated doses on the patient. The main investigator for this trial was Dr. Christian Jorgensen from Lapeyronie University Hospital in Montpellier, France.
Osteoarthritis (OA) is the most common musculoskeletal condition in adults and it can cause a good deal of pain and disability.
Joints like the knee consist of a junction between two or more bones. The ends of these bones are capped by layer of cartilage called “hyaline cartilage” that serves as a shock absorber. Larger joints like the knee, shoulder, and hip are encased in a sac called the “bursa” that is filled with lubricating synovial fluid.
OA involves damage and/or destruction of the cartilage caps at the ends of long bones, and erosion and ultimately permanent changes in the structure of bone that underlies the cartilage at the end of the bone. The knee loses its shock absorbers and lubricators and becomes a grinding, inflamed, painful caricature of its former self.
To treat OA, most orthopedic surgeons will replace the damaged knee with an artificial knee that is attached the upper (femur) and lower (tibia and fibula) bones of the leg. This procedure, arthroplasty, reconstructs the knee with artificial materials that form synthetic joints. Alternatively, some enterprising physicians have tried to use stem cells from bone marrow to repair eroded cartilage in the knees of OA patients. Christopher Centeno and his colleagues at his clinic near Denver, CO and affiliated sites have pioneered procedures for OA patients. However, Dr. Centeno remains skeptical of the ability of stem cells from fat to treat patients with OA.
In animal studies, OA of the knee can be induced by injected tissue-destroying enzymes. If laboratory mice that received injectionof these enzymes into their knees are then treated with fat-based mesenchymal stem cells, the effects and symptoms of OA do not appear (ter Huurne M, et al. Arthritis Rheum 2012; 64:3604-3613). In another study in rabbits, injections of 2-6 million fat-derived mesenchymal stem cells into the knee-joint of rabbits suffering from OA improved cartilage health and inhibited cartilage degradation. These administered cells also reduced inflammation in the knee (Desando G., et al., Arthritis Res Ther 2013; 15:R22). Therefore, fat-based mesenchymal stem seem to have some ability to ameliorate the effects and consequences of OA, at least in preclinical studies. This trial is the beginnings of what will hopefully be a series of experiments that will assess the ability (or inability) to treat OA patients.
18 patients were enrolled from an initial pool of 48 candidates who all suffered from severe, symptomatic OA of the knee. Six patients received 2 million mesenchymal stem cells isolated from their own fat, 6 others received ten million mesenchymal stem cells isolated from their own fat, and the final group of 6 OA patients received 50 million mesenchymal stem cells isolated from their own fat tissues. These mesenchymal stem cells were isolated from the patient’s fat that was collected by means of liposuction. The fat was then processed by means of a standard protocol that is used to isolated mesenchymal stem cells from human fat (see Bura A, et al., Cytotherapy 2014; 16:245-257). All patients received their stem cells by means of injection into the knee-joint (inter-articular injections).
Because this is a Phase I clinical trial, assessing the safety of the procedure is one of the main goals of this study. No adverse effects were associated with either the liposuction or the interarticular injections. The article even states: “Laboratory tests, vital signs and electrocardiograms indicated no local or systemic safety concerns.”. Four patients experienced slight knee pain and joint effusion that either resolved by itself or with treatment with a nonsteroidal antinflammatory drug (think ibuprofen). Therefore it seems fair to conclude that this procedure seems safe, but a larger, placebo-controlled study is still required to confirm this.
As to the patient’s clinical outcomes, 17 of the 18 patients elected to forego total knee replacement. All patients showed improvement in pain and knee functionality at 1 week, 3 months and 6 months after the procedure. However, only the low-dose group showed improvements that were statistically significant.
WOMAC pain and function improvement during the study. Abbreviation: WOMAC, Western Ontario and McMaster Universities Arthritis Index.
Seven of the patients treated in Germany (11 patients were treated in France and 7 were treated in Germany) were also examined with Magnetic Resonance Imaging (MRI) before and 4 months after the procedure. Six of the seven patients showed what could be interpreted as improvements in cartilage.
dGEMRIC and T1rho magnetic resonance imaging (MRI) of selected patients. The graphs on the left show the dGEMRIC (n = 6) and T1rho (n = 5) values before and 4 months after cell therapy. Increasing dGEmRIC and decreasing T1rho values are each known to correspond to increasing glycosaminoglycan/proteoglycan content and thus improved cartilage condition. On the right, the corresponding dGEMRIC and T1rho maps are shown as a color-coded overlay on an anatomical MRI for a patient receiving a low cell dose. The observed values in the cartilage change in the time course can be easily seen and correspond to an increase in cartilage condition. Abbreviation: dGEMRIC, delayed gadolinium-enhanced magnetic resonance imaging of cartilage.
Tissue biopsies of 11 of the 18 patients revealed an absence of significant inflammation, but some patients (4-5) showed signs of weak or moderate inflammation. One patient showed what seemed to be a sheet of MSC cells on the surface of the cartilage.
Histologic findings. (A): Vascular congestion and weak lymphocytic infiltrate of the synovial (case 8) (magnification, ×50). (B): Osteoarthritic cartilage OARSI grade >3 (case 4) (×25). (C): Toluidine blue staining (case 2) (magnification, ×100). (D): Stem cell stroma shows an Alcian blue depleted matrix compared with the strong staining of osteoarthritic cartilage (case 2) (magnification, ×100). (E): Weak PS100 staining of possible stem cells on the cartilage surface and strong PS100 staining of chondrocytes (case 2) (magnification, ×100). Abbreviations: OARSI, Osteoarthritis Research Society International.
The primary outcome of this study – the safety of interarticular injections of fat0-based mesenchymal stem cells – seems to have been satisfied. This is similar to the safety profiles of such cells in clinical trials that have used fat-based mesenchymal stem cells to treat fistulae in inflammatory bowel disease (Bura A, et al., Cytotherapy 2014; 16: 245-257) or critical limb ischemia (Lee WY and others, Stem Cells 2013; 31:2575-2581). Also, patients showed improvements in pain and functionality. Even though there was no placebo in this study, a double-blinded, placebo-controlled study that examined the use of efficacy of interarticular hyaluronic acid injections showed a smaller decreased in pain score that what was observed in this case (22.9 ± 1.4 vs 30.7 ± 10.7). It is doubtful that the injected mesenchymal stem cells made much cartilage but instead quelled inflammation and stimulated resident stem cell populations to repair damage in the knee.
This study is small and is not placebo controlled, however, the hopeful results do warrant a larger, phase 1/2 placebo-controlled study that is apparently already underway.
An even more intriguing project might be to prime the isolated mesenchymal stem cells to make cartilage and then use live fluoroscopy to overlay the cells on the actual cartilage lesions. While this is a more exacting procedure, it is the way Centeno and his group are using stem cells to treat their patients, and a true head-to-head study of the efficacy of fat-based mesenchymal stem cells versus bone marrow-based mesenchymal stem cells would be immensely useful.