Allogeneic Mesenchymal Stem Cells Stimulate Cartilage Regeneration and Are Safe for Single-Stage Cartilage Repair in Humans upon Mixture with Recycled Autologous Chondrons

Abstract

Traditionally, mesenchymal stem cells (MSCs) isolated from adult bone marrow were described as being capable of differentiating to various lineages including cartilage. Despite increasing interest in these MSCs, concerns regarding their safety, in vivo behavior and clinical effectiveness have restrained their clinical application. We hypothesized that MSCs have trophic effects that stimulate recycled chondrons (chondrocytes with their native pericellular matrix) to regenerate cartilage. Searching for a proof of principle, this phase I (first-in-man) clinical trial applied allogeneic MSCs mixed with either 10% or 20% recycled autologous cartilage-derived cells (chondrons) for treatment of cartilage defects in the knee in symptomatic cartilage defect patients. This unique first in man series demonstrated no treatment-related adverse events up to one year postoperatively. At 12 months, all patients showed statistically significant improvement in clinical outcome compared to baseline. Magnetic resonance imaging and second-look arthroscopies showed completely filled defects with regenerative cartilage tissue. Histological analysis on biopsies of the grafts indicated hyaline-like regeneration with a high concentration of proteoglycans and type II collagen. Short tandem repeat analysis showed the regenerative tissue only contained patient-own DNA. These findings support the novel insight that the use of allogeneic MSCs is safe and opens opportunities for other applications. Stem cell-induced paracrine mechanisms may play an important role in the chondrogenesis and successful tissue regeneration found. STEM CELLS 2017;35:256-264 SIGNIFICANCE STATEMENTThis is the first study showing allogeneic MSCs are safe and effective in stimulating cartilage regeneration in the knee when combined with autologous chondrons. The fact that one year after surgery, no stem cell DNA could be traced in the regenerative tissue, may confirm the recent view on MSCs as cellular moderators, that stimulate autologous tissue repair through paracrine mechanisms.

Response to: Mesenchymal Stem Cells: Time to Change the Name!

“…For example, while trophic factors excreted by MSCs seem to inhibit scar formation and apoptosis, the role of extracellular vesicle excretion and their amelioration of inflammation is only just recently being explored [8]. Although there is evidence that MSCs can remain traceable after several weeks in vivo, it is unclear how implanted cells behave in the human being [9].Based on our clinical work and supported by the signaling cell hypothesis, we assessed the presence of donor DNA from allogeneic MSCs 12 months after implantation in cartilage defects in the knee [10]. In this first-in-human trial, allogeneic MSCs were mixed with autologous recycled chondrons and implanted within a single surgery.…”

“…Based on our clinical work and supported by the signaling cell hypothesis, we assessed the presence of donor DNA from allogeneic MSCs 12 months after implantation in cartilage defects in the knee [10]. In this first-in-human trial, allogeneic MSCs were mixed with autologous recycled chondrons and implanted within a single surgery.…”

Quality of Life of Elderly and Obese Animal Models with Severe Knee Osteoarthritis after a Single Injection of Mesenchymal Stem Cells

“…Attempting to provide a new simple treatment of MSC therapy is needed. Although, stem cell therapy in OA knee has been studied in many previous works, most of them focus their attention on the neo-cartilage tissue regeneration [12,14,22,37,38], which may not be a main interest in older patients. In contrast, stem cell therapy based on quality of life instead of tissue regeneration would become advantageous and a major interest of OA treatment in older patients.…”

Emerging potential of gene silencing approaches targeting anti-chondrogenic factors for cell-based cartilage repair

“…Ideally, this is achieved by implanting a sufficient number of mature chondrocytes or undifferentiated progenitor cells with a high chondrogenic potential [6]. Recently, experimental therapies using mesenchymal stem cells (MSCs) have been receiving an increasing amount of interest, mostly due to the ease of isolation and their regenerative potential [7][8][9]. Unfortunately, the use of native unaltered chondrogenic cells, either chondrocytes or MSCs, has not fulfilled expectations, with the underlying mechanisms of tissue regeneration still poorly understood [10].…”