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Editorial Commentary: Stem Cells. They Are in the Fat Tissue, Bone Marrow, and Even in the Synovial Fluid of the Knee Joint

      Abstract

      Adult stem cells have been isolated in bone marrow and adipose tissue. These mesenchymal stromal cells (MSCs) have the ability to differentiate into osteogenic, chondrogenic, and adipogenic cell lines. The study by Branch et al. has identified MSCs in the synovial fluid of the knee in patients after anterior cruciate ligament injury and in patients with osteoarthritis of the knee. When mixing synovial fluid with whole blood and using a commercially available platelet-rich plasma–processing system, the total number of MSCs doubled in both groups when compared with the cell count in synovial fluid only. However, it is not clear whether the MSCs in the processed synovium–whole blood mix include synovial MSCs versus MSCs from only the blood. In addition, cell counts were substantially lower when compared with the typical concentrations of MSCs in bone marrow aspirate. The clinical application is yet to be defined.
      It seems that the hype about stem cells will continue into the foreseeable future. Promises that stem cell treatment of acute and chronic musculoskeletal conditions can restore our joints back to normal often are offered by “stem clinics” around the world. Not surprisingly, the global stem cell market is projected to reach a market valuation of nearly $22 billion US dollars by 2022.
      • Ng M.
      • Song S.
      • Piuzzi N.S.
      • et al.
      Stem cell industry update: 2012 to 2016 reveals accelerated investment, but market capitalization and earnings lag.
      So far, stem cells for clinical use have been derived mainly from bone marrow aspirate or adipose-derived stem cells.
      • Piuzzi N.S.
      • Emara A.
      • Chahla J.
      • Mandelbaum B.R.
      Ethical and practical considerations for integrating cellular (“stem cell”) therapy into clinical practice.
      ,
      • Zamborsky R.
      • Kilian M.
      • Csobonyeiiova M.
      • Danisovic L.
      Regenerative medicine in orthopaedics and trauma: Challenges, regulation and ethical issues.
      Strictly speaking, stem cells are pluripotent, undifferentiated stem cells that can differentiate into any cell line.
      • Hynes K.
      • Menicanin D.
      • Mrozik K.
      • Gronthos S.
      • Bartold P.M.
      Generation of functional mesenchymal stem cells from different induced pluripotent stem cell lines.
      When activated, a stem cell undergoes division and gives rise to one daughter stem cell and one progenitor cell; the progenitor cell then divides into a differentiated cell line.
      • Nadig R.R.
      Stem cell therapy—Hype or hope? A review.
      Adult stem cells are multipotent and can differentiate into more than one cell but not to all cell types.
      • Nadig R.R.
      Stem cell therapy—Hype or hope? A review.
      When we hear or read about stem cells in orthopaedics, it is the adult stem cell or more specifically the mesenchymal stem or stromal cell (MSC) that is normally meant. These MSCs can differentiate into mesenchymal cell lines: osteogenic, chondrogenic, and adipogenic cell lines.
      • Hynes K.
      • Menicanin D.
      • Mrozik K.
      • Gronthos S.
      • Bartold P.M.
      Generation of functional mesenchymal stem cells from different induced pluripotent stem cell lines.
      How are stem cells identified? In general, specific surface markers are used and the current thoughts are that MSCs must display at least the following cell surface markers: CD105, CD73, and CD90.
      • Hynes K.
      • Menicanin D.
      • Mrozik K.
      • Gronthos S.
      • Bartold P.M.
      Generation of functional mesenchymal stem cells from different induced pluripotent stem cell lines.
      ,
      • Dominici M.
      • Le Blanc K.
      • Mueller I.
      • et al.
      Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.
      The presence of CD45, CD34, CD14 or CD11b, CD79a, or CD19 and HLA class II suggests that the isolated cells are not MSCs.
      • Hynes K.
      • Menicanin D.
      • Mrozik K.
      • Gronthos S.
      • Bartold P.M.
      Generation of functional mesenchymal stem cells from different induced pluripotent stem cell lines.
      ,
      • Dominici M.
      • Le Blanc K.
      • Mueller I.
      • et al.
      Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.
      In the study titled “Platelet-Rich Plasma Can Be Used to Isolate Stem Cells From Synovial Fluid at the Point of Care” by Branch, Matuska, Plummer, Harrison, and Anz, the authors have isolated MSCs from synovial fluid in patients after acute anterior cruciate ligament (ACL) injury and also in patients with knee osteoarthritis.
      • Branch E.A.
      • Matuska A.M.
      • Plummer H.
      • Harrison R.M.
      • Anz A.W.
      Platelet-rich plasma can be used to isolate stem cells from synovial fluid at the point of care.
      They collected synovial fluid, combined it with whole blood, and used a commercially available platelet-rich plasma (PRP)-processing system to concentrate them.
      • Branch E.A.
      • Matuska A.M.
      • Plummer H.
      • Harrison R.M.
      • Anz A.W.
      Platelet-rich plasma can be used to isolate stem cells from synovial fluid at the point of care.
      In my understanding of the study, colony-forming unit (CFU) assays were then used to establish the presence of MSCs in the different fluid fractions. And this is where it becomes really interesting. In both the ACL-deficient and osteoarthritis group, CFUs were observed but the between-group differences were not significant. After creating the processed synovium–whole blood mix, the numbers of CFUs doubled in both groups. And, the logical conclusion was that “multipotent viable stem cells can be harvested from knee synovial fluid from patients after an ACL injury and in patients with osteoarthritis of the knee.”
      • Branch E.A.
      • Matuska A.M.
      • Plummer H.
      • Harrison R.M.
      • Anz A.W.
      Platelet-rich plasma can be used to isolate stem cells from synovial fluid at the point of care.
      In addition, by using a buffy coat–based PRP-processing device, these cells can then be concentrated.
      • Branch E.A.
      • Matuska A.M.
      • Plummer H.
      • Harrison R.M.
      • Anz A.W.
      Platelet-rich plasma can be used to isolate stem cells from synovial fluid at the point of care.
      However, there might be ambiguity here. Undoubtedly, there are MSCs in the synovial fluid, but can adding whole blood and processing using a commercially available PRP system concentrate these cells further? One of the major confounders of this study is the fact that MSCs also have been isolated from peripheral blood alone.
      • Ouryazdanpanah N.
      • Dabiri S.
      • Derakhshani A.
      • Vahidi R.
      • Farsinejad A.
      Peripheral blood-derived mesenchymal stem cells: Growth factor-free isolation, molecular characterization and differentiation.
      ,
      • Zvaifler N.J.
      • Marinova-Mutafchieva L.
      • Adams G.
      • et al.
      Mesenchymal precursor cells in the blood of normal individuals.
      Samples were mixed with 55 mL of whole blood, which exceeded the total volume of synovial fluid in the ACL-deficient (mean of 36 mL) and the osteoarthritic patient (mean of 21 mL). Could the measured number of MSCs finally result entirely from the blood without a contribution of cells from the synovial fluid? This is of course theoretically possible, but one would assume that at least some of the MSCs are definitely from the synovial fluid.
      However, let us believe for a moment that we could use a simple and straightforward commercially PRP-processing system, aspirate synovial fluid, mix it with whole blood, and use it as “PRP” with the added advantage of MSCs for various applications. Unfortunately, the mixture may not be a great improvement on PRP alone, or on the use of bone marrow aspirate, because the CFU counts observed in this study were quite low. Moreover, when compared with cell counts from bone marrow aspirates, the mixture contained only 15% to 20% of cells typically observed in bone marrow,
      • Hernigou P.
      • Homma Y.
      • Lachaniette C.H.F.
      • et al.
      Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells.
      ,
      • Beitzel K.
      • McCarthy M.B.
      • Cote M.P.
      • et al.
      Comparison of mesenchymal stem cells (osteoprogenitors) harvested from proximal humerus and distal femur during arthroscopic surgery.
      and even in bone marrow, the concentration of stem cells is extremely low, ranging from 0.01% to 0.001%.
      • Pittenger M.F.
      • Mackay A.M.
      • Beck S.C.
      • et al.
      Multilineage potential of adult human mesenchymal stem cells.
      ,
      • Chahla J.
      • Piuzzi N.S.
      • Mitchell J.J.
      • et al.
      Intra-articular cellular therapy for osteoarthritis and focal cartilage defects of the knee: A systematic review of the literature and study quality analysis.
      Of course, it could be argued that some stem cells are better than nothing, but so far there is no proof.
      There is no doubt that stem cell treatment may have substantial benefits, but the current scientific evidence is insufficient to make any recommendations. Basic science studies are still required to shine light on the mechanisms of action of MSCs, and clinical studies with a control arm are then needed to establish clinical efficiency. Until then, we should be critical and continue with proven concepts. That said, this innovative, “point-of-care” study by Branch et al. provides meritorious proof of concept: there are stem cells in the synovial fluid.

      Supplementary Data

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