Mesenchymal stem cells (MSCs) have become a promising tool in cellular therapy for restoring immune system haemostasis; however, the success of clinical trials has been impaired by the lack of standardized manufacturing processes. This study aims to determine the suitability of source tissues and culture media for the production of MSC-based advanced therapy medicinal products (ATMPs) and to define parameters to extend the set of release criteria. MSCs were isolated from umbilical cord (UC), bone marrow and lipoaspirate and expanded in three different culture media. MSC phenotype, proliferation capacity and immunosuppressive parameters were evaluated in normal MSCs compared to primed MSCs treated with cytokines mimicking an inflammatory environment. Compared to bone marrow and lipoaspirate, UC-derived MSCs (UC-MSCs) showed the highest proliferative capacity, which was further enhanced by media supplemented with bFGF, while the cells maintained their immunosuppressive characteristics. Moreover, UC-MSCs expanded in the bFGF-enriched medium were the least sensitive to undesirable priming-induced changes in the MSC phenotype. Surface markers and secreted factors were identified to reflect the cell response to inflammatory priming and to be variable among MSCs from different source tissues. This study demonstrates that UC is a favorable cell source for manufacturing MSC-based ATMPs for immunosuppressive applications. UC-MSCs are able to use the bFGF-enriched medium for higher cell yields without the impairment of immunosuppressive parameters and undesirable phenotype changes after inflammatory preconditioning of MSCs before transplantation. Additionally, immunosuppressive parameters were identified to help finding predictors of clinically efficient MSCs in the following clinical trials.

Department of Histology and Embryology Faculty of Medicine Masaryk University Kamenice 5 62500 Brno Czech Republic

International Clinical Research Center St Anne's University Hospital Pekarska 53 65691 Brno Czech Republic

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Horwitz E.M., Le Blanc K., Dominici M., Mueller I., Slaper-Cortenbach I., Marini F.C., Deans R.J., Krause D.S., Keating A., Therapy I.S.f.C. Clarification of the nomenclature for msc: The international society for cellular therapy position statement. Cytotherapy. 2005;7:393–395. doi: 10.1080/14653240500319234. PubMed DOI

Pittenger M.F., Mackay A.M., Beck S.C., Jaiswal R.K., Douglas R., Mosca J.D., Moorman M.A., Simonetti D.W., Craig S., Marshak D.R. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–147. doi: 10.1126/science.284.5411.143. PubMed DOI

Dominici M., Le Blanc K., Mueller I., Slaper-Cortenbach I., Marini F., Krause D., Deans R., Keating A., Prockop D., Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy. 2006;8:315–317. doi: 10.1080/14653240600855905. PubMed DOI

Friedenstein A.J., Petrakova K.V., Kurolesova A.I., Frolova G.P. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968;6:230–247. doi: 10.1097/00007890-196803000-00009. PubMed DOI

Chu D.T., Nguyen Thi Phuong T., Tien N.L.B., Tran D.K., Minh L.B., Thanh V.V., Gia Anh P., Pham V.H., Thi Nga V. Adipose tissue stem cells for therapy: An update on the progress of isolation, culture, storage, and clinical application. J. Clin. Med. 2019;8:917. doi: 10.3390/jcm8070917. PubMed DOI PMC

Arutyunyan I., Elchaninov A., Makarov A., Fatkhudinov T. Umbilical cord as prospective source for mesenchymal stem cell-based therapy. Stem Cells Int. 2016;2016:6901286. doi: 10.1155/2016/6901286. PubMed DOI PMC

Choi Y.S., Park Y.B., Ha C.W., Kim J.A., Heo J.C., Han W.J., Oh S.Y., Choi S.J. Different characteristics of mesenchymal stem cells isolated from different layers of full term placenta. PLoS ONE. 2017;12:e0172642. doi: 10.1371/journal.pone.0172642. PubMed DOI PMC

Ledesma-Martínez E., Mendoza-Núñez V.M., Santiago-Osorio E. Mesenchymal stem cells derived from dental pulp: A review. Stem Cells Int. 2016;2016:4709572. doi: 10.1155/2016/4709572. PubMed DOI PMC

Al-Nbaheen M., Vishnubalaji R., Ali D., Bouslimi A., Al-Jassir F., Megges M., Prigione A., Adjaye J., Kassem M., Aldahmash A. Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. Stem Cell Rev. Rep. 2013;9:32–43. doi: 10.1007/s12015-012-9365-8. PubMed DOI PMC

Sangeetha K.N., Vennila R., Secunda R., Sakthivel S., Pathak S., Jeswanth S., Surendran R. Functional variations between mesenchymal stem cells of different tissue origins: A comparative gene expression profiling. Biotechnol. Lett. 2020;42:1287–1304. doi: 10.1007/s10529-020-02898-x. PubMed DOI

Chen J.Y., Mou X.Z., Du X.C., Xiang C. Comparative analysis of biological characteristics of adult mesenchymal stem cells with different tissue origins. Asian Pac. J. Trop. Med. 2015;8:739–746. doi: 10.1016/j.apjtm.2015.07.022. PubMed DOI

Kozlowska U., Krawczenko A., Futoma K., Jurek T., Rorat M., Patrzalek D., Klimczak A. Similarities and differences between mesenchymal stem/progenitor cells derived from various human tissues. World J. Stem Cells. 2019;11:347–374. doi: 10.4252/wjsc.v11.i6.347. PubMed DOI PMC

Stenderup K., Justesen J., Clausen C., Kassem M. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone. 2003;33:919–926. doi: 10.1016/j.bone.2003.07.005. PubMed DOI

Mueller S.M., Glowacki J. Age-related decline in the osteogenic potential of human bone marrow cells cultured in three-dimensional collagen sponges. J. Cell Biochem. 2001;82:583–590. doi: 10.1002/jcb.1174. PubMed DOI

Nishida S., Endo N., Yamagiwa H., Tanizawa T., Takahashi H.E. Number of osteoprogenitor cells in human bone marrow markedly decreases after skeletal maturation. J. Bone Miner. Metab. 1999;17:171–177. doi: 10.1007/s007740050081. PubMed DOI

Kern S., Eichler H., Stoeve J., Klüter H., Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24:1294–1301. doi: 10.1634/stemcells.2005-0342. PubMed DOI

Zuk P.A., Zhu M., Ashjian P., De Ugarte D.A., Huang J.I., Mizuno H., Alfonso Z.C., Fraser J.K., Benhaim P., Hedrick M.H. Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell. 2002;13:4279–4295. doi: 10.1091/mbc.e02-02-0105. PubMed DOI PMC

Saccardi R., Mancardi G.L., Solari A., Bosi A., Bruzzi P., Di Bartolomeo P., Donelli A., Filippi M., Guerrasio A., Gualandi F., et al. Autologous hsct for severe progressive multiple sclerosis in a multicenter trial: Impact on disease activity and quality of life. Blood. 2005;105:2601–2607. doi: 10.1182/blood-2004-08-3205. PubMed DOI

Di Nicola M., Carlo-Stella C., Magni M., Milanesi M., Longoni P.D., Matteucci P., Grisanti S., Gianni A.M. Human bone marrow stromal cells suppress t-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99:3838–3843. doi: 10.1182/blood.V99.10.3838. PubMed DOI

Tse W.T., Pendleton J.D., Beyer W.M., Egalka M.C., Guinan E.C. Suppression of allogeneic t-cell proliferation by human marrow stromal cells: Implications in transplantation. Transplantation. 2003;75:389–397. doi: 10.1097/01.TP.0000045055.63901.A9. PubMed DOI

Gao X., Song L., Shen K., Wang H., Qian M., Niu W., Qin X. Bone marrow mesenchymal stem cells promote the repair of islets from diabetic mice through paracrine actions. Mol. Cell Endocrinol. 2014;388:41–50. doi: 10.1016/j.mce.2014.03.004. PubMed DOI

Del Fattore A., Luciano R., Pascucci L., Goffredo B.M., Giorda E., Scapaticci M., Fierabracci A., Muraca M. Immunoregulatory effects of mesenchymal stem cell-derived extracellular vesicles on t lymphocytes. Cell Transplant. 2015;24:2615–2627. doi: 10.3727/096368915X687543. PubMed DOI

Ren G., Zhang L., Zhao X., Xu G., Zhang Y., Roberts A.I., Zhao R.C., Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–150. doi: 10.1016/j.stem.2007.11.014. PubMed DOI

Ti D., Hao H., Fu X., Han W. Mesenchymal stem cells-derived exosomal micrornas contribute to wound inflammation. Sci. China Life Sci. 2016;59:1305–1312. doi: 10.1007/s11427-016-0240-4. PubMed DOI

Negi N., Griffin M.D. Effects of mesenchymal stromal cells on regulatory t cells: Current understanding and clinical relevance. Stem Cells. 2020;38:596–605. doi: 10.1002/stem.3151. PubMed DOI PMC

Krampera M., Galipeau J., Shi Y., Tarte K., Sensebe L., MSC Committee of the International Society for Cellular Therapy (ISCT) Immunological characterization of multipotent mesenchymal stromal cells--the international society for cellular therapy (isct) working proposal. Cytotherapy. 2013;15:1054–1061. doi: 10.1016/j.jcyt.2013.02.010. PubMed DOI

Chinnadurai R., Copland I.B., Patel S.R., Galipeau J. Ido-independent suppression of t cell effector function by ifn-γ-licensed human mesenchymal stromal cells. J. Immunol. 2014;192:1491–1501. doi: 10.4049/jimmunol.1301828. PubMed DOI

Chinnadurai R., Copland I.B., Garcia M.A., Petersen C.T., Lewis C.N., Waller E.K., Kirk A.D., Galipeau J. Cryopreserved mesenchymal stromal cells are susceptible to t-cell mediated apoptosis which is partly rescued by ifnγ licensing. Stem Cells. 2016;34:2429–2442. doi: 10.1002/stem.2415. PubMed DOI PMC

Chinnadurai R., Rajan D., Ng S., McCullough K., Arafat D., Waller E.K., Anderson L.J., Gibson G., Galipeau J. Immune dysfunctionality of replicative senescent mesenchymal stromal cells is corrected by ifnγ priming. Blood Adv. 2017;1:628–643. doi: 10.1182/bloodadvances.2017006205. PubMed DOI PMC

Rovira Gonzalez Y.I., Lynch P.J., Thompson E.E., Stultz B.G., Hursh D.A. In vitro cytokine licensing induces persistent permissive chromatin at the indoleamine 2,3-dioxygenase promoter. Cytotherapy. 2016;18:1114–1128. doi: 10.1016/j.jcyt.2016.05.017. PubMed DOI PMC

Pourgholaminejad A., Aghdami N., Baharvand H., Moazzeni S.M. The effect of pro-inflammatory cytokines on immunophenotype, differentiation capacity and immunomodulatory functions of human mesenchymal stem cells. Cytokine. 2016;85:51–60. doi: 10.1016/j.cyto.2016.06.003. PubMed DOI

Gorin C., Rochefort G.Y., Bascetin R., Ying H., Lesieur J., Sadoine J., Beckouche N., Berndt S., Novais A., Lesage M., et al. Priming dental pulp stem cells with fibroblast growth factor-2 increases angiogenesis of implanted tissue-engineered constructs through hepatocyte growth factor and vascular endothelial growth factor secretion. Stem Cells Transl. Med. 2016;5:392–404. doi: 10.5966/sctm.2015-0166. PubMed DOI PMC

Sivanathan K.N., Rojas-Canales D.M., Hope C.M., Krishnan R., Carroll R.P., Gronthos S., Grey S.T., Coates P.T. Interleukin-17a-induced human mesenchymal stem cells are superior modulators of immunological function. Stem Cells. 2015;33:2850–2863. doi: 10.1002/stem.2075. PubMed DOI

Lim J., Lee S., Ju H., Kim Y., Heo J., Lee H.Y., Choi K.C., Son J., Oh Y.M., Kim I.G., et al. Valproic acid enforces the priming effect of sphingosine-1 phosphate on human mesenchymal stem cells. Int. J. Mol. Med. 2017;40:739–747. doi: 10.3892/ijmm.2017.3053. PubMed DOI PMC

Fujisawa K., Takami T., Okada S., Hara K., Matsumoto T., Yamamoto N., Yamasaki T., Sakaida I. Analysis of metabolomic changes in mesenchymal stem cells on treatment with desferrioxamine as a hypoxia mimetic compared with hypoxic conditions. Stem Cells. 2018;36:1226–1236. doi: 10.1002/stem.2826. PubMed DOI

Takeda K., Ning F., Domenico J., Okamoto M., Ashino S., Kim S.H., Jeong Y.Y., Shiraishi Y., Terada N., Sutherland E.R., et al. Activation of p70s6 kinase-1 in mesenchymal stem cells is essential to lung tissue repair. Stem Cells Transl. Med. 2018;7:551–558. doi: 10.1002/sctm.17-0200. PubMed DOI PMC

Popa M.A., Mihai M.C., Constantin A., Şuică V., Ţucureanu C., Costache R., Antohe F., Dubey R.K., Simionescu M. Dihydrotestosterone induces pro-angiogenic factors and assists homing of msc into the cardiac tissue. J. Mol. Endocrinol. 2018;60:1–15. doi: 10.1530/JME-17-0185. PubMed DOI

Lee J.H., Yoon Y.M., Lee S.H. Hypoxic preconditioning promotes the bioactivities of mesenchymal stem cells via the hif-1α-grp78-akt axis. Int. J. Mol. Sci. 2017;18:1320. doi: 10.3390/ijms18061320. PubMed DOI PMC

Lee S.G., Joe Y.A. Autophagy mediates enhancement of proangiogenic activity by hypoxia in mesenchymal stromal/stem cells. Biochem. Biophys. Res. Commun. 2018;501:941–947. doi: 10.1016/j.bbrc.2018.05.086. PubMed DOI

Li B., Li C., Zhu M., Zhang Y., Du J., Xu Y., Liu B., Gao F., Liu H., Cai J., et al. Hypoxia-induced mesenchymal stromal cells exhibit an enhanced therapeutic effect on radiation-induced lung injury in mice due to an increased proliferation potential and enhanced antioxidant ability. Cell Physiol. Biochem. 2017;44:1295–1310. doi: 10.1159/000485490. PubMed DOI

Sun X., Su W., Ma X., Zhang H., Sun Z., Li X. Comparison of the osteogenic capability of rat bone mesenchymal stem cells on collagen, collagen/hydroxyapatite, hydroxyapatite and biphasic calcium phosphate. Regen. Biomater. 2018;5:93–103. doi: 10.1093/rb/rbx018. PubMed DOI PMC

Chen S., Shi J., Zhang M., Chen Y., Wang X., Zhang L., Tian Z., Yan Y., Li Q., Zhong W., et al. Mesenchymal stem cell-laden anti-inflammatory hydrogel enhances diabetic wound healing. Sci. Rep. 2015;5:18104. doi: 10.1038/srep18104. PubMed DOI PMC

Khan M., Ali F., Mohsin S., Akhtar S., Mehmood A., Choudhery M.S., Khan S.N., Riazuddin S. Preconditioning diabetic mesenchymal stem cells with myogenic medium increases their ability to repair diabetic heart. Stem Cell Res. Ther. 2013;4:58. doi: 10.1186/scrt207. PubMed DOI PMC

Jossen V., van den Bos C., Eibl R., Eibl D. Manufacturing human mesenchymal stem cells at clinical scale: Process and regulatory challenges. Appl. Microbiol. Biotechnol. 2018;102:3981–3994. doi: 10.1007/s00253-018-8912-x. PubMed DOI PMC

Tozetti P.A., Caruso S.R., Mizukami A., Fernandes T.R., da Silva F.B., Traina F., Covas D.T., Orellana M.D., Swiech K. Expansion strategies for human mesenchymal stromal cells culture under xeno-free conditions. Biotechnol. Prog. 2017;33:1358–1367. doi: 10.1002/btpr.2494. PubMed DOI

Mizukami A., Fernandes-Platzgummer A., Carmelo J.G., Swiech K., Covas D.T., Cabral J.M., da Silva C.L. Stirred tank bioreactor culture combined with serum-/xenogeneic-free culture medium enables an efficient expansion of umbilical cord-derived mesenchymal stem/stromal cells. Biotechnol. J. 2016;11:1048–1059. doi: 10.1002/biot.201500532. PubMed DOI

Cunha B., Aguiar T., Carvalho S.B., Silva M.M., Gomes R.A., Carrondo M.J.T., Gomes-Alves P., Peixoto C., Serra M., Alves P.M. Bioprocess integration for human mesenchymal stem cells: From up to downstream processing scale-up to cell proteome characterization. J. Biotechnol. 2017;248:87–98. doi: 10.1016/j.jbiotec.2017.01.014. PubMed DOI

Timmins N.E., Kiel M., Günther M., Heazlewood C., Doran M.R., Brooke G., Atkinson K. Closed system isolation and scalable expansion of human placental mesenchymal stem cells. Biotechnol. Bioeng. 2012;109:1817–1826. doi: 10.1002/bit.24425. PubMed DOI

Mizukami A., Orellana M.D., Caruso S.R., de Lima Prata K., Covas D.T., Swiech K. Efficient expansion of mesenchymal stromal cells in a disposable fixed bed culture system. Biotechnol. Prog. 2013;29:568–572. doi: 10.1002/btpr.1707. PubMed DOI

Haack-Sørensen M., Follin B., Juhl M., Brorsen S.K., Søndergaard R.H., Kastrup J., Ekblond A. Culture expansion of adipose derived stromal cells. A closed automated quantum cell expansion system compared with manual flask-based culture. J. Transl. Med. 2016;14:319. doi: 10.1186/s12967-016-1080-9. PubMed DOI PMC

Lambrechts T., Papantoniou I., Rice B., Schrooten J., Luyten F.P., Aerts J.M. Large-scale progenitor cell expansion for multiple donors in a monitored hollow fibre bioreactor. Cytotherapy. 2016;18:1219–1233. doi: 10.1016/j.jcyt.2016.05.013. PubMed DOI

Nold P., Brendel C., Neubauer A., Bein G., Hackstein H. Good manufacturing practice-compliant animal-free expansion of human bone marrow derived mesenchymal stroma cells in a closed hollow-fiber-based bioreactor. Biochem. Biophys. Res. Commun. 2013;430:325–330. doi: 10.1016/j.bbrc.2012.11.001. PubMed DOI

Rojewski M.T., Fekete N., Baila S., Nguyen K., Fürst D., Antwiler D., Dausend J., Kreja L., Ignatius A., Sensebé L., et al. Gmp-compliant isolation and expansion of bone marrow-derived mscs in the closed, automated device quantum cell expansion system. Cell Transplant. 2013;22:1981–2000. doi: 10.3727/096368912X657990. PubMed DOI

Hanley P.J., Mei Z., Durett A.G., Cabreira-Hansen M.a.G., Cabreira-Harrison M.a.G., Klis M., Li W., Zhao Y., Yang B., Parsha K., et al. Efficient manufacturing of therapeutic mesenchymal stromal cells with the use of the quantum cell expansion system. Cytotherapy. 2014;16:1048–1058. doi: 10.1016/j.jcyt.2014.01.417. PubMed DOI PMC

Guess A.J., Daneault B., Wang R., Bradbury H., La Perle K.M.D., Fitch J., Hedrick S.L., Hamelberg E., Astbury C., White P., et al. Safety profile of good manufacturing practice manufactured interferon γ-primed mesenchymal stem/stromal cells for clinical trials. Stem Cells Transl. Med. 2017;6:1868–1879. doi: 10.1002/sctm.16-0485. PubMed DOI PMC

Li W.J., Tuli R., Okafor C., Derfoul A., Danielson K.G., Hall D.J., Tuan R.S. A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells. Biomaterials. 2005;26:599–609. doi: 10.1016/j.biomaterials.2004.03.005. PubMed DOI

Apel A., Groth A., Schlesinger S., Bruns H., Schemmer P., Büchler M.W., Herr I. Suitability of human mesenchymal stem cells for gene therapy depends on the expansion medium. Exp. Cell Res. 2009;315:498–507. doi: 10.1016/j.yexcr.2008.11.013. PubMed DOI

Sotiropoulou P.A., Perez S.A., Salagianni M., Baxevanis C.N., Papamichail M. Characterization of the optimal culture conditions for clinical scale production of human mesenchymal stem cells. Stem Cells. 2006;24:462–471. doi: 10.1634/stemcells.2004-0331. PubMed DOI

Bahsoun S., Coopman K., Akam E.C. The impact of cryopreservation on bone marrow-derived mesenchymal stem cells: A systematic review. J. Transl. Med. 2019;17:397. doi: 10.1186/s12967-019-02136-7. PubMed DOI PMC

Lin Y., Hogan W.J. Clinical application of mesenchymal stem cells in the treatment and prevention of graft-versus-host disease. Adv. Hematol. 2011;2011:427863. doi: 10.1155/2011/427863. PubMed DOI PMC

Subbanna P.K. Mesenchymal stem cells for treating gvhd: In-vivo fate and optimal dose. Med. Hypotheses. 2007;69:469–470. doi: 10.1016/j.mehy.2006.12.016. PubMed DOI

Guan Y.T., Xie Y., Li D.S., Zhu Y.Y., Zhang X.L., Feng Y.L., Chen Y.P., Xu L.J., Liao P.F., Wang G. Comparison of biological characteristics of mesenchymal stem cells derived from the human umbilical cord and decidua parietalis. Mol. Med. Rep. 2019;20:633–639. doi: 10.3892/mmr.2019.10286. PubMed DOI PMC

Beeravolu N., Khan I., McKee C., Dinda S., Thibodeau B., Wilson G., Perez-Cruet M., Bahado-Singh R., Chaudhry G.R. Isolation and comparative analysis of potential stem/progenitor cells from different regions of human umbilical cord. Stem Cell Res. 2016;16:696–711. doi: 10.1016/j.scr.2016.04.010. PubMed DOI

Ramasamy R., Tong C.K., Yip W.K., Vellasamy S., Tan B.C., Seow H.F. Basic fibroblast growth factor modulates cell cycle of human umbilical cord-derived mesenchymal stem cells. Cell Prolif. 2012;45:132–139. doi: 10.1111/j.1365-2184.2012.00808.x. PubMed DOI PMC

Nekanti U., Mohanty L., Venugopal P., Balasubramanian S., Totey S., Ta M. Optimization and scale-up of wharton’s jelly-derived mesenchymal stem cells for clinical applications. Stem Cell Res. 2010;5:244–254. doi: 10.1016/j.scr.2010.08.005. PubMed DOI

Jin H.J., Bae Y.K., Kim M., Kwon S.J., Jeon H.B., Choi S.J., Kim S.W., Yang Y.S., Oh W., Chang J.W. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int. J. Mol. Sci. 2013;14:17986–18001. doi: 10.3390/ijms140917986. PubMed DOI PMC

Heo J.S., Choi Y., Kim H.S., Kim H.O. Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue. Int. J. Mol. Med. 2016;37:115–125. doi: 10.3892/ijmm.2015.2413. PubMed DOI PMC

Lin C.S., Ning H., Lin G., Lue T.F. Is cd34 truly a negative marker for mesenchymal stromal cells? Cytotherapy. 2012;14:1159–1163. doi: 10.3109/14653249.2012.729817. PubMed DOI PMC

Sakaguchi Y., Sekiya I., Yagishita K., Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source. Arthritis Rheum. 2005;52:2521–2529. doi: 10.1002/art.21212. PubMed DOI

Rebelatto C.K., Aguiar A.M., Moretão M.P., Senegaglia A.C., Hansen P., Barchiki F., Oliveira J., Martins J., Kuligovski C., Mansur F., et al. Dissimilar differentiation of mesenchymal stem cells from bone marrow, umbilical cord blood, and adipose tissue. Exp. Biol. Med. 2008;233:901–913. doi: 10.3181/0712-RM-356. PubMed DOI

Saparov A., Ogay V., Nurgozhin T., Jumabay M., Chen W.C. Preconditioning of human mesenchymal stem cells to enhance their regulation of the immune response. Stem Cells Int. 2016;2016:3924858. doi: 10.1155/2016/3924858. PubMed DOI PMC

Lee M.W., Ryu S., Kim D.S., Sung K.W., Koo H.H., Yoo K.H. Strategies to improve the immunosuppressive properties of human mesenchymal stem cells. Stem Cell Res. Ther. 2015;6:179. doi: 10.1186/s13287-015-0178-y. PubMed DOI PMC

Amati E., Sella S., Perbellini O., Alghisi A., Bernardi M., Chieregato K., Lievore C., Peserico D., Rigno M., Zilio A., et al. Generation of mesenchymal stromal cells from cord blood: Evaluation of in vitro quality parameters prior to clinical use. Stem Cell Res. Ther. 2017;8:14. doi: 10.1186/s13287-016-0465-2. PubMed DOI PMC

Bassi G., Guilloton F., Menard C., Di Trapani M., Deschaseaux F., Sensebé L., Schrezenmeier H., Giordano R., Bourin P., Dominici M., et al. Effects of a ceramic biomaterial on immune modulatory properties and differentiation potential of human mesenchymal stromal cells of different origin. Tissue Eng. Part. A. 2015;21:767–781. doi: 10.1089/ten.tea.2014.0269. PubMed DOI PMC

Shi Y., Su J., Roberts A.I., Shou P., Rabson A.B., Ren G. How mesenchymal stem cells interact with tissue immune responses. Trends Immunol. 2012;33:136–143. doi: 10.1016/j.it.2011.11.004. PubMed DOI PMC

Espagnolle N., Balguerie A., Arnaud E., Sensebé L., Varin A. Cd54-mediated interaction with pro-inflammatory macrophages increases the immunosuppressive function of human mesenchymal stromal cells. Stem Cell Rep. 2017;8:961–976. doi: 10.1016/j.stemcr.2017.02.008. PubMed DOI PMC

Wang Y., Huang J., Gong L., Yu D., An C., Bunpetch V., Dai J., Huang H., Zou X., Ouyang H., et al. The plasticity of mesenchymal stem cells in regulating surface hla-i. iScience. 2019;15:66–78. doi: 10.1016/j.isci.2019.04.011. PubMed DOI PMC

Fu X., Chen Y., Xie F.N., Dong P., Liu W.B., Cao Y., Zhang W.J., Xiao R. Comparison of immunological characteristics of mesenchymal stem cells derived from human embryonic stem cells and bone marrow. Tissue Eng. Part. A. 2015;21:616–626. doi: 10.1089/ten.tea.2013.0651. PubMed DOI PMC

Yagi H., Soto-Gutierrez A., Parekkadan B., Kitagawa Y., Tompkins R.G., Kobayashi N., Yarmush M.L. Mesenchymal stem cells: Mechanisms of immunomodulation and homing. Cell Transplant. 2010;19:667–679. doi: 10.3727/096368910X508762. PubMed DOI PMC

Li X., Xu Z., Bai J., Yang S., Zhao S., Zhang Y., Chen X., Wang Y. Umbilical cord tissue-derived mesenchymal stem cells induce t lymphocyte apoptosis and cell cycle arrest by expression of indoleamine 2, 3-dioxygenase. Stem Cells Int. 2016;2016:7495135. doi: 10.1155/2016/7495135. PubMed DOI PMC

Dabrowski F.A., Burdzinska A., Kulesza A., Sladowska A., Zolocinska A., Gala K., Paczek L., Wielgos M. Comparison of the paracrine activity of mesenchymal stem cells derived from human umbilical cord, amniotic membrane and adipose tissue. J. Obstet. Gynaecol. Res. 2017;43:1758–1768. doi: 10.1111/jog.13432. PubMed DOI

Li C.Y., Wu X.Y., Tong J.B., Yang X.X., Zhao J.L., Zheng Q.F., Zhao G.B., Ma Z.J. Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xeno-free conditions for cell therapy. Stem Cell Res. Ther. 2015;6:55. doi: 10.1186/s13287-015-0066-5. PubMed DOI PMC

Ozaki K., Sato K., Oh I., Meguro A., Tatara R., Muroi K., Ozawa K. Mechanisms of immunomodulation by mesenchymal stem cells. Int. J. Hematol. 2007;86:5–7. doi: 10.1532/IJH97.07003. PubMed DOI

Groh M.E., Maitra B., Szekely E., Koç O.N. Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive t cells. Exp. Hematol. 2005;33:928–934. doi: 10.1016/j.exphem.2005.05.002. PubMed DOI

Nasef A., Chapel A., Mazurier C., Bouchet S., Lopez M., Mathieu N., Sensebé L., Zhang Y., Gorin N.C., Thierry D., et al. Identification of il-10 and tgf-beta transcripts involved in the inhibition of t-lymphocyte proliferation during cell contact with human mesenchymal stem cells. Gene Expr. 2007;13:217–226. doi: 10.3727/000000006780666957. PubMed DOI PMC

Tomic S., Djokic J., Vasilijic S., Vucevic D., Todorovic V., Supic G., Colic M. Immunomodulatory properties of mesenchymal stem cells derived from dental pulp and dental follicle are susceptible to activation by toll-like receptor agonists. Stem Cells Dev. 2011;20:695–708. doi: 10.1089/scd.2010.0145. PubMed DOI

Ouchi T., Nakagawa T. Mesenchymal stem cell-based tissue regeneration therapies for periodontitis. Regen. Ther. 2020;14:72–78. doi: 10.1016/j.reth.2019.12.011. PubMed DOI PMC

Song H., Kwon K., Lim S., Kang S.M., Ko Y.G., Xu Z., Chung J.H., Kim B.S., Lee H., Joung B., et al. Transfection of mesenchymal stem cells with the fgf-2 gene improves their survival under hypoxic conditions. Mol. Cells. 2005;19:402–407. PubMed

Prasanna S.J., Gopalakrishnan D., Shankar S.R., Vasandan A.B. Pro-inflammatory cytokines, ifngamma and tnfalpha, influence immune properties of human bone marrow and wharton jelly mesenchymal stem cells differentially. PLoS ONE. 2010;5:e9016. doi: 10.1371/journal.pone.0009016. PubMed DOI PMC

Manochantr S., U-pratya Y., Kheolamai P., Rojphisan S., Chayosumrit M., Tantrawatpan C., Supokawej A., Issaragrisil S. Immunosuppressive properties of mesenchymal stromal cells derived from amnion, placenta, wharton’s jelly and umbilical cord. Intern. Med. J. 2013;43:430–439. doi: 10.1111/imj.12044. PubMed DOI

Truncated vitronectin with E-cadherin enables the xeno-free derivation of human embryonic stem cells

Facing the Challenges in the COVID-19 Pandemic Era: From Standard Treatments to the Umbilical Cord-Derived Mesenchymal Stromal Cells as a New Therapeutic Strategy

In vitro effects of conditioned medium from bioreactor cultured human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) on skin-derived cell lines