Mesenchymal stromal cells (MSCs) are a top candidate for new clinical treatments in the repair of bone and cartilage. In several clinical trials, they have shown reliable, effective, and safe management of inflammation, pain, and the regenerative capabilities of resident tissues. MSCs are likely derived from pericytes. They modulate the environment they are placed in by secreting immunomodulatory and signaling molecules to reduce inflammation and direct resident cells to create new tissues. They are easily isolated from several different adult tissues, and inexpensive to grow in a lab. However, a mistake made in the initial classification of MSCs as stem cells has created deeply engrained misconceptions that are still evident today. MSCs are not stem cells, despite a large fraction of research and therapies using the name “mesenchymal stem cells”. This mistake creates false narratives attributing the observed positive outcomes of MSC treatments to stem cell characteristics, which has led to distrust in MSC research. Despite inconsistencies in their classification, MSCs demonstrate consistent positive effects in numerous animal studies and human clinical trials for non-unions and osteoarthritis. With an aging population, regenerative techniques are very promising for novel therapies. To produce trusted and safe new treatments using MSCs, it is essential for the International Society for Cellular Therapies to re-establish common ground in the identity, mechanism of action, and isolation techniques of these cells.
References
[1]
Calori, G.M., Mazza, E.L., Mazzola, S., Colombo, A., Giardina, F., Romanó, F. and Colombo, M. (2017) Non-Unions. Clinical Cases in Mineral and Bone Metabolism, 14, 186.
[2]
Kong, L., Zheng, L.Z., Qin, L.,and Ho, K.K.W. (2017) Role of Mesenchymal Stem Cells in Osteoarthritis Treatment. Journal of Orthopedic Translation, 9, 89-103. https://doi.org/10.1016/j.jot.2017.03.006
Dominici, M., Le Blanc, K., Mueller, I., Slaper-Cortenbach, I., Marini, F.C., Krause, D.S., Deans, R., Keating, A., Prockop, D. and Horwitz, E.M. (2006) Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. Cytotherapy, 8, 315-317. https://doi.org/10.1080/14653240600855905
[5]
Crisan, M., Yap, S., Casteilla, L., Chen, C.W., Corselli, M., Park, T.S., Andriolo, G., Sun, B., Zheng, B., Zhang, L., Norotte, C., Teng, P.N., Traas, J. Schugar, R., Deasy, B.M., Badylak, S., Búhring, J., Giacobino, J.P., Lazzari, L., Péault, B., et al. (2008) A Perivascular Origin for Mesenchymal Stem Cells in Multiple Human Organs. Cell Stem Cell, 3, 301-313. https://doi.org/10.1016/j.stem.2008.07.003
[6]
Da Silva Meirelles, L., Malta, T.M., De Deus Wagatsuma, V.M., Palma, P.V., Araújo, A.G., Ribeiro Malmegrim, K.C., Morato De Oliveira, F., Panepucci, R.A., Silva Jr., W.A., Haddad, S.K. and Covas, D.T. (2015) Cultured Human Adipose Tissue Pericytes and Mesenchymal Stromal Cells Display a Very Similar Gene Expression Profile. Stem Cells and Development, 24, 2822-2840. https://doi.org/10.1089/scd.2015.0153
[7]
Guimarães-Camboa, N., Cattaneo, P., Sun, Y., Moore-Morris, T., Gu, Y., Dalton, N. D., Rockenstein, E., Masliah, E., Peterson, K.L., Stallup, W.B., Chen, J. and Evans, S.M. (2017) Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells in Vivo. Cell Stem Cell, 20, 345-359.E5. https://doi.org/10.1016/j.stem.2016.12.006
[8]
Caplan, A.I. (2017) Mesenchymal Stem Cells: Time to Change the Name! STEM CELLS Translational Medicine, 6, 1445-1451. https://doi.org/10.1002/sctm.17-0051
[9]
Sacchetti, B., Funari, A., Remoli, C., Giannicola, G., Kogler, G., Liedtke, S., Cossu, G., Serafini, M., Sampaolesi, M., Tagliafico, E., Tenedini, E., Saggio, I., Robey, P.G., Riminucci, M. and Bianco, P. (2016). No Identical “Mesenchymal Stem Cells” at Different Times and Sites: Human Committed Progenitors of Distinct Origin and Differentiation Potential Are Incorporated as Adventitial Cells in Microvessels. Stem Cell Reports, 6, 897-913. https://doi.org/10.1016/j.stemcr.2016.05.011
[10]
Bianco, P. and Robey, P.G. (2015) Skeletal Stem Cells. Development, 142, 1023-1027. https://doi.org/10.1242/dev.102210
[11]
Ambrosi, T.H., Longaker, M.T. and Chan, C.K. (2019) A Revised Perspective of Skeletal Stem Cell Biology. Frontiers in Cell and Developmental Biology, 7, Article 478752. https://doi.org/10.3389/fcell.2019.00189
[12]
Da Silva Meirelles, L., Fontes, A.M., Covas, D.T. and Caplan, A.I. (2009) Mechanisms Involved in the Therapeutic Properties of Mesenchymal Stem Cells. Cytokine & Growth Factor Reviews, 20, 419-427. https://doi.org/10.1016/j.cytogfr.2009.10.002
[13]
Chan, C.K.F., Gulati, G.S., Sinha, R., Tompkins, J.V., Lopez, M., Carter, A.C., Ransom, R.C., Reinisch, A., Wearda, T., Murphy, M., Brewer, R.E., Koepke, L.S., Marecic, O., Manjunath, A., Seo, E.Y., Leavitt, T., Lu, W.J., Nguyen, A., Conley, S.D., Longaker, M.T., et al. (2018) Identification of the Human Skeletal Stem Cell. Cell, 175, 43-56.E21. https://doi.org/10.1016/j.cell.2018.07.029
[14]
Granero-Moltó, F., Weis, J.A., Miga, M.I., Landis, B., Myers, T.J., O’Rear, L., Longobardi, L., Jansen, E.D., Mortlock, D.P. and Spagnoli, A. (2009) Regenerative Effects of Transplanted Mesenchymal Stem Cells in Fracture Healing. Stem Cells, 27, 1887-1898. https://doi.org/10.1002/stem.103
[15]
Xu, L., Huang, S., Hou, Y., Liu, Y., Ni, M., Meng, F., Wang, K., Rui, Y., Jiang, X. and Li, G. (2014). Sox11-Modified Mesenchymal Stem Cells (MSCs) Accelerate Bone Fracture Healing: Sox11 Regulates Differentiation and Migration of MSCs. The FASEB Journal, 29, 1143-1152. https://doi.org/10.1096/fj.14-254169
[16]
Van Der Stok, J., Koolen, M.K.E., Jahr, H., Kops, N., Waarsing, J.H., Weinans, H. and Van Der Jagt, O.P. (2014) Chondrogenically Differentiated Mesenchymal Stromal Cell Pellets Stimulate Endochondral Bone Regeneration in Critical-Sized Bone Defects. European Cells and Materials, 27, 137-148. https://doi.org/10.22203/eCM.v027a11
[17]
Gómez-Barrena, E., Rosset, P., Gebhard, F., Hernigou, P., Baldini, N., Rouard, H., Sensebé, L., Gonzal-Daganzo, R.M., Giordano, R., Padilla-Eguiluz, N., García-Rey, E., Cordero-Ampuero, J., Rubio-Suárez, J.C., Stanovici, J., Enrnthaller, C., Huber-Lang, M., Flouzat-Lachaniette, C.H., Chevallier, N., Donati, D.M., Layrolle, P., et al. (2019) Feasibility and Safety of Treating Non-Unions in Tibia, Femur and Humerus with Autologous, Expanded, Bone Marrow-Derived Mesenchymal Stromal Cells Associated with Biphasic Calcium Phosphate Biomaterials in a Multicentric, Non-Comparative Trial. Biomaterials, 196, 100-108. https://doi.org/10.1016/j.biomaterials.2018.03.033
[18]
Wang, C.Y., Yang, H.B., Hsu, H.S., Chen, L.L., Tsai, C.C., Tsai, K.S., Yew, T.L., Kao, Y.H. and Hung, S.C. (2011). Mesenchymal Stem Cell-Conditioned Medium Facilitates Angiogenesis and Fracture Healing in Diabetic Rats. Journal of Tissue Engineering and Regenerative Medicine, 6, 559-569. https://doi.org/10.1002/term.461
Jo, C.H., Lee, Y.G., Shin, W.H., Kim, H., Chai, J.W., Jeong, E.C., Kim, J.E., Shim, H., Shin, J.S., Shin, I.S., Ra, J.C., Oh, S. and Yoon, K.S. (2014) Intra-Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A Proof-Of-Concept Clinical Trial. Stem Cells, 32, 1254-1266. https://doi.org/10.1002/stem.1634
[21]
Lee, W., Kim, H., Kim, K., Kim, G. and Jin, W. (2019) Intra-Articular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Phase IIb, Randomized, Placebo-Controlled Clinical Trial. Stem Cells Translational Medicine, 8, 504-511. https://doi.org/10.1002/sctm.18-0122
[22]
Davatchi, F., Sadeghi Abdollahi, B., Mohyeddin, M. and Nikbin, B. (2015) Mesenchymal Stem Cell Therapy for Knee Osteoarthritis: 5 Years Follow-Up of Three Patients. International Journal of Rheumatic Diseases, 19, 219-225. https://doi.org/10.1111/1756-185X.12670
[23]
Matas, J., Orrego, M., Amenabar, D., Infante, C., Tapia-Limonchi, R., Cadiz, M.I., Alcayaga-Miranda, F., González, P.L., Muse, E., Khoury, M., Figueroa, F.E. and Espinoza, F. (2018) Umbilical Cord-Derived Mesenchymal Stromal Cells (MSCs) for Knee Osteoarthritis: Repeated MSC Dosing Is Superior to a Single MSC Dose and to Hyaluronic Acid in a Controlled Randomized Phase I/II Trial. Stem Cells Translational Medicine, 8, 215-224. https://doi.org/10.1002/sctm.18-0053
[24]
Barrachina, L., Cequier, A., Romero, A., Vitoria, A., Zaragoza, P., Vázquez, F.J. and Rodellar, C. (2020) Allo-Antibody Production after Intraarticular Administration of Mesenchymal Stem Cells (MSCs) in an Equine Osteoarthritis Model: Effect of Repeated Administration, MSC Inflammatory Stimulation, and Equine Leukocyte Antigen (ELA) Compatibility. Stem Cell Research & Therapy, 11, Article No. 52. https://doi.org/10.1186/s13287-020-1571-8
[25]
Ichiseki, T., Shimasaki, M., Ueda, Y., Ueda, S., Tsuchiya, M., Souma, D., Kaneuji, D. and Kawahara, N. (2018) Intraarticularly-Injected Mesenchymal Stem Cells Stimulate Anti-Inflammatory Molecules and Inhibit Pain Related Protein and Chondrolytic Enzymes in a Monoiodoacetate-Induced Rat Arthritis Model. International Journal of Molecular Sciences, 19, Article 203. https://doi.org/10.3390/ijms19010203
[26]
Kim, Y.S., Chung, P.K., Suh, D.S., Heo, D.B., Tak, D.H. and Koh, Y.G. (2019) Implantation of Mesenchymal Stem Cells in Combination with Allogenic Cartilage Improves Cartilage Regeneration and Clinical Outcomes in Patients with Concomitant High Tibial Osteotomy. Knee Surgery, Sports Traumatology, Arthroscopy, 28, 544-554. https://doi.org/10.1007/s00167-019-05729-3
[27]
Zhang, X., Yamaoka, K., Sonomoto, K., Kaneko, H., Satake, M., Yamamoto, Y., Masahiro, K., Zhao, J., Miyajawa, I., Yamagata, K., Fukuyo, S., Okada, Y. and Tanaka, Y. (2014) Local Delivery of Mesenchymal Stem Cells with Poly-Lactic-Co-Glycolic Acid Nano-Fiber Scaffold Suppress Arthritis in Rats. PLOS ONE, 9, e114621. https://doi.org/10.1371/journal.pone.0114621
[28]
Qi, Y., Du, Y., Li, W., Dai, X., Zhao, T. and Yan, W. (2012) Cartilage Repair Using Mesenchymal Stem Cell (MSC) Sheet and MSCs-Loaded Bilayer PLGA Scaffold in A Rabbit Model. Knee Surgery, Sports Traumatology, Arthroscopy, 22, 1424-1433. https://doi.org/10.1007/s00167-012-2256-3
[29]
Qazi, T.H., Mooney, D.J., Duda, G.N. and Geissler, S. (2017) Biomaterials That Promote Cell-Cell Interactions Enhance the Paracrine Function of MSCs. Biomaterials, 140, 103-114. https://doi.org/10.1016/j.biomaterials.2017.06.019
[30]
Zhang, X., Liu, S., Wang, Z., Luo, C., Dai, Z., Sun, J., Liu, Y., Shao, Z., Yang, S., Wang, H., Wang, J., Chen, W., Zhang, Y., Xu, W., Tian, H. and Tong, W. (2021) Implanted 3D Gelatin Microcryogel Enables Low-Dose Cell Therapy for Osteoarthritis By Preserving the Viability and Function of Umbilical Cord MSCs. Chemical Engineering Journal, 416, Article ID: 129140. https://doi.org/10.1016/j.cej.2021.129140
[31]
Mithoefer, K., McAdams, T., Williams, R.J., Kreuz, P.C. and Mandelbaum, B.R. (2009) Clinical Efficacy of the Microfracture Technique for Articular Cartilage Repair in the Knee. The American Journal of Sports Medicine, 37, 2053-2063. https://doi.org/10.1177/0363546508328414
[32]
Hashimoto, Y., Nishida, Y., Takahashi, S., Nakamura, H., Mera, H., Kashiwa, K., Yoshiya, S., Inagaki, Y., Uematsu, K., Tanaka, Y., Asada, S., Akagi, M., Fukuda, K., Yoshiya, S., Myoui, A., Kamei, N., Ishikawa, M., Adachi, N., Ochi, M. and Wakitani, S. (2019) Transplantation of Autologous Bone Marrow-Derived Mesenchymal Stem Cells under Arthroscopic Surgery with Microfracture versus Microfracture Alone for Articular Cartilage Lesions in the Knee: A Multicenter Prospective Randomized Control Clinical Trial. Regenerative Therapy, 11, 106-113. https://doi.org/10.1016/j.reth.2019.06.002
