{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:46:01Z","timestamp":1792759561421,"version":"4.5.0"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T00:00:00Z","timestamp":1631577600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Mesenchymal stem cells (MSCs) are accessible, abundantly available, and capable of regenerating; they have the potential to be developed as therapeutic agents for diseases. However, concerns remain in their further application. In this study, we developed a SMall cell+Ultra Potent+Scale UP cell (SMUP-Cell) platform to improve whole-cell processing, including manufacturing bioreactors and xeno-free solutions for commercialization. To confirm the superiority of SMUP-Cell improvements, we demonstrated that a molecule secreted by SMUP-Cells is capable of polarizing inflammatory macrophages (M1) into their anti-inflammatory phenotype (M2) at the site of injury in a pain-associated osteoarthritis (OA) model. Lipopolysaccharide-stimulated macrophages co-cultured with SMUP-Cells expressed low levels of M1-phenotype markers (CD11b, tumor necrosis factor-\u03b1, interleukin-1\u03b1, and interleukin-6), but high levels of M2 markers (CD163 and arginase-1). To identify the paracrine action underlying the anti-inflammatory effect of SMUP-Cells, we employed a cytokine array and detected increased levels of pentraxin-related protein-3 (PTX-3). Additionally, PTX-3 mRNA silencing was applied to confirm PTX-3 function. PTX-3 silencing in SMUP-Cells significantly decreased their therapeutic effects against monosodium iodoacetate (MIA)-induced OA. Thus, PTX-3 expression in injected SMUP-Cells, applied as a therapeutic strategy, reduced pain in an OA model.<\/jats:p>","DOI":"10.3390\/cells10092420","type":"journal-article","created":{"date-parts":[[2021,9,14]],"date-time":"2021-09-14T23:34:11Z","timestamp":1631662451000},"page":"2420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["PTX-3 Secreted by Intra-Articular-Injected SMUP-Cells Reduces Pain in an Osteoarthritis Rat Model"],"prefix":"10.3390","volume":"10","author":[{"given":"Minju","family":"Lee","sequence":"first","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0394-4077","authenticated-orcid":false,"given":"Gee-Hye","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0497-8148","authenticated-orcid":false,"given":"Miyeon","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Min","family":"Seo","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu Mi","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi Ra","family":"Seon","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0034-114X","authenticated-orcid":false,"given":"Soyoun","family":"Um","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2914-6797","authenticated-orcid":false,"given":"Soo Jin","family":"Choi","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wonil","family":"Oh","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo Ram","family":"Song","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hye Jin","family":"Jin","sequence":"additional","affiliation":[{"name":"Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam-si 13494, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1038\/s41536-019-0083-6","article-title":"Mesenchymal Stem Cell Perspective: Cell Biology to Clinical Progress","volume":"4","author":"Pittenger","year":"2019","journal-title":"NPJ Regen. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1007\/s00402-020-03349-y","article-title":"Human Umbilical Cord Blood-Derived Mesenchymal Stem Cell Implantation for Osteoarthritis of the Knee","volume":"140","author":"Song","year":"2020","journal-title":"Arch. Orthop. Trauma. Surg."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ichiseki, T., Shimazaki, M., Ueda, Y., Ueda, S., Tsuchiya, M., Souma, D., Kaneuji, A., 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. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010203"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1511","DOI":"10.4252\/wjsc.v12.i12.1511","article-title":"Prospects for the Therapeutic Development of Umbilical Cord Blood-Derived Mesenchymal Stem Cells","volume":"12","author":"Um","year":"2020","journal-title":"World J. Stem Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"364","DOI":"10.3389\/fcell.2020.00364","article-title":"Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges","volume":"8","author":"Zhou","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.jbiotec.2017.01.014","article-title":"Bioprocess Integration for Human Mesenchymal Stem Cells: From up to Downstream Processing Scale-Up to Cell Proteome Characterization","volume":"248","author":"Cunha","year":"2017","journal-title":"J. Biotechnol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"9415367","DOI":"10.1155\/2018\/9415367","article-title":"Bioprocessing of Mesenchymal Stem Cells and Their Derivatives: Toward Cell-Free Therapeutics","volume":"2018","author":"Phelps","year":"2018","journal-title":"Stem Cells Int."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s40169-017-0168-z","article-title":"Optimization of Culture Conditions for Rapid Clinical-Scale Expansion of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells","volume":"6","author":"Choi","year":"2017","journal-title":"Clin. Transl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2672","DOI":"10.1038\/s41375-018-0151-8","article-title":"Small Hypoxia-Primed Mesenchymal Stem Cells Attenuate Graft-Versus-Host Disease","volume":"32","author":"Kim","year":"2018","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5924983","DOI":"10.1155\/2020\/5924983","article-title":"A Small-Sized Population of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Shows High Stemness Properties and Therapeutic Benefit","volume":"2020","author":"Kim","year":"2020","journal-title":"Stem Cells Int."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kwon, J.H., Kim, M., Um, S., Lee, H.J., Bae, Y.K., Choi, S.J., Hwang, H.H., Oh, W., and Jin, H.J. (2021). Senescence-Associated Secretory Phenotype Suppression Mediated by Small-Sized Mesenchymal Stem Cells Delays Cellular Senescence Through TLR2 and TLR5 Signaling. Cells, 10.","DOI":"10.3390\/cells10010063"},{"key":"ref_12","first-page":"1705","article-title":"Destruction of the Articular Cartilage in Osteoarthritis","volume":"23","author":"Okubo","year":"2013","journal-title":"Clin. Calcium."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"16044","DOI":"10.1038\/boneres.2016.44","article-title":"Osteoarthritis: Toward a Comprehensive Understanding of Pathological Mechanism","volume":"5","author":"Chen","year":"2017","journal-title":"Bone Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.joca.2013.03.018","article-title":"The Epidemiology and Impact of Pain in Osteoarthritis","volume":"21","author":"Neogi","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nrrheum.2016.65","article-title":"Ageing and the Pathogenesis of Osteoarthritis","volume":"12","author":"Loeser","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"284873","DOI":"10.1155\/2013\/284873","article-title":"The Role of Changes in Extracellular Matrix of Cartilage in the Presence of Inflammation on the Pathology of Osteoarthritis","volume":"2013","author":"Maldonado","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Riegger, J., and Brenner, R.E. (2020). Pathomechanisms of Posttraumatic Osteoarthritis: Chondrocyte Behavior and Fate in a Precarious Environment. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051560"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.bej.2015.07.015","article-title":"Evaluation of a Monitored Multiplate Bioreactor for Large-Scale Expansion of Human Periosteum Derived Stem Cells for Bone Tissue Engineering Applications","volume":"108","author":"Lambrechts","year":"2016","journal-title":"Biochem. Eng. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"427","DOI":"10.5966\/sctm.2015-0109","article-title":"Downregulation of Melanoma Cell Adhesion Molecule (MCAM\/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells","volume":"5","author":"Jin","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Bae, Y.K., Kwon, J.H., Kim, M., Kim, G.H., Choi, S.J., Oh, W., and Jeon, H.B. (2018). Intracellular Calcium Determines the Adipogenic Differentiation Potential of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells via the Wnt5a\/\u03b2-Catenin Signaling Pathway. Stem Cells International, 1\u201317.","DOI":"10.1155\/2018\/6545071"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1097\/j.pain.0000000000001466","article-title":"Contribution of Synovial Macrophages to Rat Advanced Osteoarthritis Pain Resistant to Cyclooxygenase Inhibitors","volume":"160","author":"Sakurai","year":"2019","journal-title":"Pain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal Criteria for Defining Multipotent Mesenchymal Stromal Cells. The International Society for Cellular Therapy Position Statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.stem.2010.01.011","article-title":"Stem Cells and the Niche: A Dynamic Duo","volume":"6","author":"Voog","year":"2010","journal-title":"Cell Stem Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1538\/expanim.17-0142","article-title":"A Rat Model of Knee Osteoarthritis Suitable for Electroacupuncture Study","volume":"67","author":"Ma","year":"2018","journal-title":"Exp. Anim."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"30881","DOI":"10.1038\/srep30881","article-title":"Mesenchymal Stem Cells Protect Against the Tissue Fibrosis of Ketamine-Induced Cystitis in Rat Bladder","volume":"6","author":"Kim","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3981","DOI":"10.1007\/s00253-018-8912-x","article-title":"Manufacturing Human Mesenchymal Stem Cells at Clinical Scale: Process and Regulatory Challenges","volume":"102","author":"Jossen","year":"2018","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s13287-019-1202-4","article-title":"A Comprehensive Characterisation of Large-Scale Expanded Human Bone Marrow and Umbilical Cord Mesenchymal Stem Cells","volume":"10","author":"Mennan","year":"2019","journal-title":"Stem Cell Res. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2374","DOI":"10.1111\/trf.14805","article-title":"Characterization and Cost\u2013Benefit Analysis of Automated Bioreactor-Expanded Mesenchymal Stem Cells for Clinical Applications","volume":"58","author":"Russell","year":"2018","journal-title":"Transfusion"},{"key":"ref_29","first-page":"762132","article-title":"Engineering Parameters in Bioreactor\u2019s Design: A Critical Aspect in Tissue Engineering","volume":"2013","author":"Amoabediny","year":"2013","journal-title":"BioMed. Res. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.jcyt.2018.10.014","article-title":"Mesenchymal Stromal Cell Therapy: Progress in Manufacturing and Assessments of Potency","volume":"21","author":"Robb","year":"2019","journal-title":"Cytotherapy."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s12934-019-1198-6","article-title":"Metabolic Fluxes-Oriented Control of Bioreactors: A Novel Approach to Tune Micro-Aeration and Substrate Feeding in Fermentations","volume":"18","author":"Mesquita","year":"2019","journal-title":"Microb. Cell Factories"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4696","DOI":"10.1038\/s41598-019-41140-1","article-title":"The Polyadenylation Inhibitor Cordycepin Reduces Pain, Inflammation and Joint Pathology in Rodent Models of Osteoarthritis","volume":"9","author":"Ashraf","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17986","DOI":"10.3390\/ijms140917986","article-title":"Comparative Analysis of Human Mesenchymal Stem Cells from Bone Marrow, Adipose Tissue, and Umbilical Cord Blood as Sources of Cell Therapy","volume":"14","author":"Jin","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13287-016-0393-1","article-title":"Effects of Matrix Metalloproteinases on the Fate of Mesenchymal Stem Cells","volume":"7","author":"Almalki","year":"2016","journal-title":"Stem Cell Res. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/s41598-017-18542-0","article-title":"Thrombospondin-1 Secreted by Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Rescues Neurons from Synaptic Dysfunction in Alzheimer\u2019s Disease Model","volume":"8","author":"Kim","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1802976","DOI":"10.1155\/2020\/1802976","article-title":"Soluble PTX3 of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Attenuates Hyperoxic Lung Injury by Activating Macrophage Polarization in Neonatal Rat Model","volume":"2020","author":"Kim","year":"2020","journal-title":"Stem Cells Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fimmu.2020.00111","article-title":"Macrophage: A Potential Target on Cartilage Regeneration","volume":"11","author":"Fernandes","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"13","DOI":"10.12703\/P6-13","article-title":"The M1 and M2 Paradigm of Macrophage Activation: Time for Reassessment","volume":"6","author":"Martinez","year":"2014","journal-title":"F1000Prime Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0299-y","article-title":"Mesenchymal stem cells prevent the progression of diabetic nephropathy by improving mitochondrial function in tubular epithelial cells","volume":"51","author":"Lee","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_40","first-page":"290","article-title":"Pentraxin-3 Regulates the Inflammatory Activity of Macrophages","volume":"5","author":"Shiraki","year":"2016","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e60086","DOI":"10.1371\/journal.pone.0060086","article-title":"Dectin-1 Regulates IL-10 Production via a MSK1\/2 and CREB Dependent Pathway and Promotes the Induction of Regulatory Macrophage Markers","volume":"8","author":"Elcombe","year":"2013","journal-title":"PLoS ONE"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"56","DOI":"10.3389\/fcell.2016.00056","article-title":"Emerging Roles of the Mitogen and Stress Activated Kinases MSK1 and MSK2","volume":"4","author":"Reyskens","year":"2016","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s10194-017-0741-2","article-title":"Calcitonin gene-related peptide and pain: A systematic review","volume":"18","author":"Schou","year":"2017","journal-title":"J. Headache. Pain."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"14055","DOI":"10.1523\/JNEUROSCI.1722-14.2014","article-title":"Multimodal Use of Calcitonin Gene-Related Peptide and Substance P in Itch and Acute Pain Uncovered by the Elimination of Vesicular Glutamate Transporter 2 from Transient Receptor Potential Cation Channel Subfamily V Member 1 Neurons","volume":"34","author":"Rogoz","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/JID.2015.346","article-title":"Mesenchymal Stromal Cell-Derived PTX3 Promotes Wound Healing via Fibrin Remodeling","volume":"136","author":"Cappuzzello","year":"2016","journal-title":"J. Invest. Dermatol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1814","DOI":"10.1002\/jnr.23616","article-title":"Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Improve Functional Recovery Through Thrombospondin1, pantraxin3, and Vascular Endothelial Growth Factor in the Ischemic Rat Brain","volume":"93","author":"Park","year":"2015","journal-title":"J. Neurosci. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40635-017-0126-5","article-title":"Intraperitoneal Adoptive Transfer of Mesenchymal Stem Cells Enhances Recovery from Acid Aspiration Acute Lung Injury in Mice","volume":"5","author":"Mauri","year":"2017","journal-title":"Intensive Care Med. Exp."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1759720X19864492","DOI":"10.1177\/1759720X19864492","article-title":"Update on Novel Pharmacological Therapies for Osteoarthritis","volume":"11","author":"Ghouri","year":"2019","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_49","first-page":"F1000","article-title":"Recent Advances in the Treatment of Osteoarthritis","volume":"9","author":"Muschter","year":"2020","journal-title":"F1000Research"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s13770-018-00176-6","article-title":"Perspective on Intra-articular Injection Cell Therapy for Osteoarthritis Treatment","volume":"16","author":"Im","year":"2019","journal-title":"Tissue. Eng. Regen. Med."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2420\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:43Z","timestamp":1760166163000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/9\/2420"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,14]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["cells10092420"],"URL":"https:\/\/doi.org\/10.3390\/cells10092420","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,14]]}}}