title: Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties.
abstract: Previous reports suggested that culture as 3D aggregates or as spheroids can increase the therapeutic potential of the adult stem/progenitor cells referred to as mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs). Here we used a hanging drop protocol to prepare human MSCs (hMSCs) as spheroids that maximally expressed TNFalpha stimulated gene/protein 6 (TSG-6), the antiinflammatory protein that was expressed at high levels by hMSCs trapped in the lung after i.v. infusion and that largely explained the beneficial effects of hMSCs in mice with myocardial infarcts. The properties of spheroid hMSCs were found to depend critically on the culture conditions. Under optimal conditions for expression of TSG-6, the hMSCs also expressed high levels of stanniocalcin-1, a protein with both antiinflammatory and antiapoptotic properties. In addition, they expressed high levels of three anticancer proteins: IL-24, TNFalpha-related apoptosis inducing ligand, and CD82. The spheroid hMSCs were more effective than hMSCs from adherent monolayer cultures in suppressing inflammatory responses in a coculture system with LPS-activated macrophages and in a mouse model for peritonitis. In addition, the spheroid hMSCs were about one-fourth the volume of hMSCs from adherent cultures. Apparently as a result, larger numbers of the cells trafficked through the lung after i.v. infusion and were recovered in spleen, liver, kidney, and heart. The data suggest that spheroid hMSCs may be more effective than hMSCs from adherent cultures in therapies for diseases characterized by sterile tissue injury and unresolved inflammation and for some cancers that are sensitive to antiinflammatory agents.
authors.affiliation: Texas A&M Health Science Center, College of Medicine, Institute for Regenerative Medicine at Scott & White, Temple, TX 76502, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Bartosh
authors.forename: Joni H
authors.initials: JH
authors.lastname: Ylöstalo
authors.forename: Arezoo
authors.initials: A
authors.lastname: Mohammadipoor
authors.forename: Nikolay
authors.initials: N
authors.lastname: Bazhanov
authors.forename: Katie
authors.initials: K
authors.lastname: Coble
authors.forename: Kent
authors.initials: K
authors.lastname: Claypool
authors.forename: Ryang Hwa
authors.initials: RH
authors.lastname: Lee
authors.forename: Hosoon
authors.initials: H
authors.lastname: Choi
authors.forename: Darwin J
authors.initials: DJ
authors.lastname: Prockop
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002449:Cell Aggregation; D002470:Cell Survival; D002478:Cells, Cultured; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D051861:Kangai-1 Protein / Q000276:immunology; D008024:Ligands; D008264:Macrophages / Q000276:immunology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D051861:Kangai-1 Protein; D008024:Ligands; C072273:TNFAIP6 protein, human; C051795:teleocalcin