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| Source of MSC | Functional properties | |
|
| Bone marrow (ref) | In-vitro | Main findings |
| 48 | Serum-free spheroids maintained MSC phenotype. High differentiation potential (3D versus 2D culture conditions). | Positive for surface markers (CD105, CD90, CD73, and CD34). Higher osteogenic, chrondogenic and adipogenic differentiation capacity. |
| 21 | High secretion of anti-inflammatory and antitumorogenic factors (3D versus 2D). MSC derived from spheroids retains the properties of 2D MSC. High anti-inflammatory effect in a mouse macrophage immune assay (3D versus 2D). | Higher secretion of TSG-6, STC1, LIF and IL-24, TRAIL. Similar proliferation, immunophenotype and differentiation potential. Higher inhibition of TNF-a secretion by macrophages. |
| 31 | MSC form sphere-like structures after i.p. injection of adherent MSC in a mouse. High gene expression of anti-inflammatory factors and IL1 as well as notch signaling molecules. Activation of caspase-dependent IL1 signaling (3D versus 2D). High anti-inflammatory effect after IL1 signaling activation. | High gene expression of COX2, TSG6, and STC1. Up-regulation of TSG-6, COX 2, STC1 and IL1 and notch related molecules. Higher secretion of IL1a, IL1b. Higher secretion of PGE2 and immunomodulatory effect on LPS stimulated macrophages. |
| 32 | Protocol for preparation of MSC spheroid. | Efficient MSC spheroids formation using hanging-drop cultures. |
| 19 | High gene expression and protein levels of immune, angiogenic and growth factors (3D versus 2D). Decreased expression of immunomodulatory factors after BMP2 treatment. High gene expression of immunomodulatory and growth factors after IL1B treatment. | Higher expression of IL1B, IL8, PTGS2/COX2, TNFAIP6, SOD2, CXCL1, CXCL2, CCL2 and CCL7, BMP2, BMP6. Lower expression of IL1B, IL8, PTGS2/COX2, TNFAIP6, SOD2, CXCL1, CXCL2, CCL2 and CCL7. Higher expression of BMP2, IL1B, IL8, LIF, PTGS2/COX2, TNFAIP6 and SOD2. |
| 40 | Increased chemotactic potential induced by conditioned medium (3D, alginate-encapsulated 3D versus 2D). Enhanced immunomodulatory potential. Enhanced angiogenic potential (alginate-encapsulated 3D versus 2D). | Higher migration of fibroblasts in the presence of alginate-encapsulated spheroids. Higher expression of TSG-6 in encapsulated and non-encapsulated spheroids. Higher proangiogenic potential. |
| 34 | Enhanced survival under ambient conditions (hESC derived-MSC, 3D versus 2D). Low cell metabolism and proliferation in ambient conditions-recovered MSC. Ambient conditions-recovered MSC retains the properties of 2D MSC. | Higher MSC survival. Lower cell metabolism and proliferation correlates to the enhanced survival. Similar gene expression, immunophenotype, differentiation and immunosuppressive potential. |
| 35 | Enhanced secretome secretion (3D versus 2D). | Higher efficiency in exosome production in larger spheroids. |
| 36 | High cartilaginous/calcium deposition. Enhanced osteoblast differentiation (3D versus 2D). | Presence of fibrous and mineralized extra-cellular matrix, micro-calcification deposits. Higher osteogenic differentiation capacity. |
| 44 | High cytokine secretion after priming with proinflammatory cytokines (3D versus 2D). High cytokine secretion after IL1 priming. High immunomodulatory effect of conditioned medium from spheroids after IL1 priming. Potent immune profile after IL1 priming (3D versus 2D). | Higher secretion of G-CSF, IL-1Ra and VEGF. Higher secretion of IL-6 and G-CSF in 24 hr conditioned media. Decreased TNF-a secretion in LPS treated BV2 microglial cells. Higher expression of MCSF, TNF-b, CC7/MCP3, Gro-a-CXCL1, CCL22, TNF-a, CCL23, IL-6, IL-19, IL-8, MIG/CXCL9 and G-CSF. |
| 20 | High immunomodulatory effect (spheroid, spheroid-derived cells and their conditioned medium versus 2D). High immunosuppressive effect of conditioned medium (3D versus 2D). High anti-inflammatory activity. | Effective suppression of TNF-a secretion in LPS-stimulated macrophages. Decreased of TNF-a, CXCL2, IL-6, IL12p40, IL-23 and increased IL-10 and IL1ra secretion. High secretion of PGE2, dependent of COX-2 and mediated by EP4 receptor. |
| 38 | Enhanced characteristics in xeno-free medium supplemented with HSA. High anti-inflammatory effect (conditioned medium). High gene expression of immunomodulatory and anti- cancer related molecules (3D versus 2D). High anti-cancer in vitro effect (spheroid-conditioned medium). | High cell viability, cell yield and small cell size. Decreased TNFα and increased IL-10 secretion by LPS-stimulated macrophages. High PGE2 and TSG-6 secretion. Higher expression of PGE2, TSG-6, TRAIL, IL-24 and lower levels of TNF-a. reduced prostate cancer cell growth (LNCaP cells). |
| 39 | High expression of anti-inflammatory and anti-cancer molecules. High anti-inflammatory and anti-cancer effect (conditioned medium). | Upregulation of PGE2, TSG-6, TRIAL and IL-24. Decreased TNFα and increased IL-10 secretion by LPS-stimulated macrophages. Decreased IFN-g production by CD3-stimulated splenocytes. Reduced prostate cancer cell growth (LNCaP cells). |
| 42 | High secretion of immunomodulatory paracrine factors (3D versus 2D). High secretion of immunomodulatory factors after TNF-a and/or IFN-g licensing (3D versus 2D and two different cell culture medium). High immunosuppressive effect after TNF-a and/or IFN-g licensing (3D versus 2D). | Higher secretion of PGE2, TGF-β1, IL-6 and similar IDO activity. Higher secretion of PGE-2, IL-6 and IDO activity in spheroids cultured in FBS media. Higher suppression of TNF-a secretion by LPS-stimulated macrophages after TNFa/IFN-g priming. |
| 43 | High sustained immunomodulatory activity (microparticle delivery of IFN-g within spheroids). High anti-inflammatory effect in a mouse macrophage assay. | High sustained IDO expression and enhanced suppression of T-cell activation and proliferation. Decreased TNFα and increased IL-10 secretion by macrophages. |
| Adipose tissue | | |
| 29 | High expression of proteins related to angiogenesis, proliferation, migration and ECM deposition (3D versus 2D). | Higher expression of fibronectin, fibrinogen, TIMP1, MMP2, TGFβ1, FGFb, IGFBP-1, EGF, HGF, VEGF, MMP14, tenascin C, and collagen VI alpha 3. |
| 51 | High cell survival and ECM molecules secretion (spheroid formation on chitosan films, 3D versus 2D). Enhanced stemness, proliferation and differentiation potential (3D versus 2D). | Higher viability and laminin and fibronectin secretion. Higher gene expression and proteins levels of Nanog, Sox-2, Oct-4. Higher expansion efficiency, colony-forming activity and osteogenic and adipogenic differentiation as well as transdifferentiation capacity. |
| 18 | Enhanced stemness, angiogenic and chemotactic potential (3D versus 2D). | Higher cell growth rate and lower senescence. Higher gene expression and protein levels of Sox2, Oct4, Nanog, HGF, and VEGF. Higher expression of CXCR4, MMP-9 ans MMP-13. |
| 49 | Enhanced apoptosis resistance and secretion of growth factors (3D versus 2D). | Higher expression of BCL2, FGF-2, VEGF. Higher BCL-2/Bax ratio. Higher protein levels of VEGF. |
| 30 | Spheroid survival potential under varying glucose and oxygen concentrations (mathematical modeling). | High linear correlation between spheroid glucose availability and viability. |
| 45 | High angiogenic potential (3D versus 2D). Enhanced resistance to anoikis (3D versus 2D). | Higher expression of VEGF, HGF, SDF-1, HIF-1a, fibronectin and laminin. Higher AKT phosphorylation and lower expression of PARP-1 and cleaved caspase-3. |
| 52 | Enhanced stemness, angiogenic and anti-inflammatory potential (spheroids prepared in a HA gel versus 2D) . | Higher gene expression of VEGFA, VEGF B, HGF, PDGFA, PDGFC, IL1RN, IL11 and NANOG, OCT3/4, STAT3 markers. Higher expression SSEA-3 stem cell marker. |
| 46 | Enhanced paracrine and regenerative effect. | High gene expression of IL-6, IL-8 and VEGF in response to hypoxia. |
| 47 | High Angiogenic and tissue regeneration potential after photobiomodulation irradiation (3D versus 2D). | Higher secretion of FGF, VEGFand HGF. Higher positivity for CD34, CD31 and KDR. |
| 37 | High regenerative, anti-apoptotic and anti-oxidative potential (3D, 3D-derived cells versus 2D). Enhanced secretion of cytokines and immunomodulatory factors (3D, 3D-derived cells versus 2D). | Higher secretion of collagen I, fibronectin, laminin. Higher expression levels of catalase, SOD-1, Bcl-2, P-akt al lower expression of cleaved Caspase3. Higher secretion of VEGF, EGF, IGF, bFGF, HGF and TSG-6. |
| Umbilical cord | | |
| 33 | Enhanced osteogenic and anti-apoptotic potential. High survival and anti-apoptotic effect under hypoxic conditions (3D versus 2D). | High production of CEGF, FGF2, HGF and Bcl-2 expression. Higher cell viability and Bcl-2 expression. |
| 50 | Enhanced stemness, proliferation and differentiation potential (3D versus 2D). | Higher expression of Klf-4, C-myc. Higher osteogenic and adipogenic differentiation potential. |
| 41 | High anti-inflammatory effect of conditioned medium (3D versus 2D). High motogenic effect of conditioned medium over mouse chondrocytes (3D versus 2D). | Higher levels of anti-inflammatory and trophic factors (IL-10, LIF, PDGF-BB, FGF-2, I-309, SCF, GM-CSF). Higher chondrocyte migration capacity. |
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