Table 1  List of in vivo studies in which the therapeutic potential of the administration of hMSCs for the treatment of GvHD and hemophagocytic syndrome was evaluated and the results obtained.
References   Autoimmune disease   Source of hMSC   Variables   Experimental model   Clinical and laboratory effects   Proposed mechanisms for the in vivo action of MSCs
(33)  GVHD  Dental pulp  Administration of MSCs alone Administration of MSCs transduced with immunosuppressive genes  Mice  ↓Clinical score↑Fatal embolism Effectiveness MSC transduced with immunosuppressive genes = effectiveness of MSCs alone  ↓Mouse splenocyte proliferation
(34)  GVHD  Fetal membrane  Administration of MSCs from amnion membrane  Mice  ↓Weight loss Effectiveness MSC from amnion membrane > effectiveness of MSCs from from chorion membrane  ↑HGF secretion↑IGF-1 secretion↑VEGF secretion↑bFGF secretion↑PGE2 secretion↓T-cell proliferation
Administration of MSCs from chorion membrane   None
(35)  GVHD  Bone marrow  Infusion of MSCs on day 0  Mice  None  ↓Donor T cell proliferation↓TNF-α
Infusion of MSCs on day 7   ↓Weight loss↑Survival rates↓Acute GvHD score↓Gut and liver pathology
Stimulation of MSCs with IFN-γ for 48 h prior to administration on day 0   ↓Weight loss↑Survival rates↓Clinical score↓Gut and liver pathology
(36)  GVHD  Umbilical cord stroma  None  Mice  ↓Clinical score↓Weight loss↑Survival rates↓Gut, skin and liver pathology  ↓CD3+CD8+ T cells↑CD4+/CD8+ ratio↓TNF-α↓IL-2↓IFN- γ↑IL-10
(37)  GVHD  Bone marrow  None  Mice  None  ↓T-cell proliferation↓IFN- γ secretion
(38)  GVHD  Umbilical cord blood  Presence of radiation-induced damage  Mice  ↓Weight loss  ↓Human/mice CD45+ cells ratio↑Human CD45+ cells total number↓Human CD3+ cells in the liver↓Human CD4+ cells in the liver
Absence of radiation-induced damage   ↓Clinical score↑Survival rates  ↓Human/mice CD45+ cells ratio↓Human CD45+ cells total number↓Human CD3+ cells in the liver↓Human CD4+ cells in the liver
(39)  GVHD  Umbilical cord stroma  Stimulation of MSCs with IFN-γ for 24 h  Mice  Not assessed  ↓CD4+ T-cell proliferation↑IDO gene expression↑TGF-β gene expression
Absence of stimulation of MSCs with IFN-γ for 24 h   ↓Clinical score↓Weight loss↑Survival rates↓Gut and liver pathology  ↑TGF-β gene expression
(40)  GVHD  Adipose tissue  Absence of stimulation of MSCs with rapamycin prior to administration Stimulation of MSCs with rapamycin prior to administration  Mice  ↓Clinical score↑Survival rates↓Weight loss Effectiveness MSCs + rapamycin > effectiveness MSCs alone  ↓CD4+IFN-γ+ Th1 cells↓CD4+IL-17+ Th17 cells↑CD4+IL-4+ Th2 cells↑CD4+CD25+Foxp3+ Treg cells
(41)  GVHD  Umbilical cord blood  Prevention study for GVHDTreatment study for GVHD  Mice  ↑Survival rates↓Weight loss↓Clinical score↓Kidney, lungs, liver and gut pathology Multiple MSCs administrations > single MSCs administration at day 0.  ↑PGE2↑TGF-β1↓IFN-γ
(48)  GVHD  Placenta  None  Mice  ↑Survival rates↓Weight loss↓Gut, skin and liver pathology  None
(59)  GVHD  Adipose tissue  Co-infusion of MSCs and Tregs Administration of MSCs alone  Mice  ↑Survival rates↓Weight loss↓Clinical score↓Gut, skin and liver pathology Effectiveness MSCs + Tregs > effectiveness MSCs alone  ↓CD3+CD4+ T-cells↓Th17 cells↑Foxp3+ Tregs cells
(61)  GVHD  Umbilical cord blood  Infusion of MSCs previously treated with rapamycinAdministration of MSCs aloneMSCs from pooled bone marrow mononuclear cells of eight “3rd-party” donors (MSCs end-products)  Mice  ↑Survival rates↓Weight loss Effectiveness MSCs + rapamycin > effectiveness MSCs alone  ↓Infiltration of human CD45+ cells in the spleen (MSCs pre-treated with rapamycin)
(72)  GVHD  Bone marrow Menstrual blood  None  Mice  ↑Survival rates↓Weight loss↓Gut and liver pathology Effectiveness MSCs from menstrual blood > effectiveness MSCs from bone marrow  ↓CD8+IFN-γ+ cells↓CD4+IFN-γ+ Th1 cells↓Th17 cells↑CD4+IL4+IL10+ T cells↑Tregs cells↑IDO↑PD-L1↑PGE2↑Activin A↑Cox-2↑IFN-γ (menstrual blood MSCs)↓Foxp3+ expression in splenocytes (menstrual blood MSCs)↑IL-6 expression↑NRP-1 expression↑HGF expression in the liver (menstrual blood MSCs)↑VEGF expression in the liver (menstrual blood MSCs)
↑CXCR4+ cells (in the menstrual blood MSCs population)↓Human CD45+ cells in spleen (bone marrow MSCs)↓Human CD45+CD8+ T cells in spleen (bone marrow MSCs)↑ Human CD45+CD8+ T cells in spleen (menstrual blood MSCs)↑ Human CD45+CD4+ T cells in spleen (menstrual blood and bone marrow MSCs)
(42)  GVHD  Bone marrow  None  Humans  ↓Dry eye symptoms↓GvHD clinical score  ↑CD8+CD28− T cells↑IL-2↑IFN-γ↓IL-10↓IL-4
(43)  GVHD  Bone marrow  None  Humans  ↑Donor engraftment↓Clinical score↓Leukemia relapse  ↑CD3+CD8+ T cell reconstitution↑CD3−CD(16+56)+ T cells reconstitution↑CD3+CD(16+56)+ T cells reconstitution
(44)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score  None
(45)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score  ↓CD3+/CD4+ T cells ratio
(46)  GVHD  Umbilical cord blood  None  Humans  ↑Donor engraftment↓Clinical score  None
(47)  GVHD  Bone marrow  None  Humans  ↑Pneumonia-related death  None
(49)  GVHD  Bone marrow  MSCs at first or second passage  Humans  ↑Survival rates↑Infection-related death Effectiveness MSCs at first or second passage > effectiveness MSCs at third or fourth passage  ↓IL-2 receptor in the serum
MSCs at third or fourth passage
(50)  GVHD  Bone marrow  None  Humans  ↓ccK18↓K18  ↑IL-2↑IL-6↓IFN-γ/IL-4 ratio↑CD4+/CD8+ ratio↓HLA-DR+CD4+ T-cells↓HLA-DR+CD8+ T-cells↑CD4+CD25med−hi CD127loFOXP3+ Treg-cells↓Th17 cells↑Treg/Th17 ratio↓CD56bright NK-cells
(51)  GVHD  Bone marrow  None  Humans  ↑Acute GVHD disease prophylaxis↑Survival rates  ↑FGF receptor gene↓PPAR-γ gene↓IGF-1 gene
(52)  GVHD  Bone marrow  None  Humans  ↓Clinical score  None
(53)  GVHD  Bone marrow  None  Humans  ↓Clinical score↓Chronic GVHD incidence  ↑CD4+/CD8+ ratio↑CD4+CD25+Foxp3+ Tregs cells↑T cell reconstitution (↑sjTRECs)
(54)  GVHD  Bone marrow  None  Humans  ↓Acute GVHD incidence↓Clinical score  None
(55)  GVHD  Bone marrow  None  Humans  ↓Nephrotic syndrome symptoms  ↓IFN-γ↓TNF-α↓CD19+ B cell↑Bregs cells↑Tregs cells
(56)  GVHD  Bone marrow  None  Humans  ↓Clinical score↑Survival rates↓Gut, skin and liver pathology  None
(57)  GVHD  Bone marrow  None  Humans  ↓Clinical score↑Survival rates  None
(58)  GVHD  Bone marrow  None  Humans  ↑Survival rates  ↑IL-2 receptor lymphocyte gene expression↑IFN- γ lymphocyte gene expression↑FoxP3 lymphocyte gene expression↑CTLA-4 lymphocyte gene expression↑IL-10 lymphocyte gene expression↑Foxp3+ Tregs cells
(60)  GVHD  Bone marrow  None  Humans  ↑Survival rates  ↑Anti-fetal calf serum antibodies↓Alloantibodies
(62)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score  None
(63)  GVHD  Bone marrow  None  Humans  ↓Clinical score↓Bilirubin concentration  None
(64)  GVHD  Bone marrow  None  Humans  ↓Clinical score↓Skin and mucosal pathology  ↓IL-1β↓IFN-γ↓TNF-α
(65)  GVHD  Umbilical cord stroma  None  Humans  ↓Chronic GVHD incidence↓Lung pathology↑Survival rates  ↑Th1/Th2 cells ratio↑Treg cells↑CD27+ memory B lymphocytes↓NK cells
(66)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Gastrointestinal acute GVHD symptoms↓Gastrointestinal pathology↓CK18↓sCK18F↓sCK18F/CK18 ratio  ↓TNF-α receptor↓IL-2 receptor
(67)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score↓Gut, skin and liver pathology  None
(68)  GVHD  Bone marrow  MSCs from single donorsMSCs from pooled bone marrow mononuclear cells of eight “3rd-party” donors (MSCs end-products)  Humans  ↑Survival rates↓Clinical score Effectiveness MSCs end-products > effectiveness MSCs from single donors  None
(69)  GVHD  Bone marrow  None  Humans  ↑Donor engraftment  ↓Donor T-cell proliferation
(70)  GVHD  Bone marrow  None  Humans  ↓Survival rates  ↓T cell reconstitution (↓TRECs)↓B cell reconstitution (↓IgM)↓IgG
(71)  GVHD  Bone marrow  None  Humans  ↑Survival rates↓Clinical score↓CK18  ↓TNF-α receptor↓Elafin↓IL-2 receptor↓Reg3α↓HGF↓IL-8↓CCL2↓CD40L↓CXCL9↓CXCL10↑NGF↑IL-10↑IL-12↑IFN-γ↑IL-15↑CCL7↑bFGF↑GM-CSF↑TNF-α↑IL-23↑Granzyme B
(52)  Hemophagocytic syndrome  Bone marrow  None  Humans  ↓Clinical score  Not assessed
(73)  Hemophagocytic syndrome  Bone marrow  None  Humans  ↓Disease severity↓Serum ferritin↓Serum triglycerides↓Serum lactate dehydrogenase  ↑IL-10↓IL-8↓IL-6↓IL-15↓IL-17↓TNF-α
Both the methodology employed and the results obtained by each article are represented in this table. HGF, hepatocyte growth factor; IGF-1, insulin like growth factor 1; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; PGE2, prostaglandin E2; TNF-α, tumor necrosis factoralpha; IL-2, interleukin-2; IL-4, interleukin-4; IL-1β, interleukin-1 beta; IL-6, interleukin-6; IL-8, interleukin-8; IL-10, interleukin-10; IL-12, interleukin-12; IL-15, interleukin-15; IL-23, interleukin-23; IDO, indoleamine-pyrrole 2,3-dioxygenase; TGF-β, transforming growth factor beta; NGF, nerve growth factor; NK cells, natural killer cells; Th1 cells, type 1 T helper cells; Th2 cells, type 2 T helper cells; Th17 cells, type 17 T helper cells; Treg cells, regulatory T cells; Bregs cells, regulatory B cells; ccK18, caspase-cleaved cytokeratin 18; K18, keratin 18; CK18, cytoskeletal keratin 18; sCK18F, soluble cytokeratin 18 fragments; PPAR-γ, peroxisome proliferator-activated receptor; sjTRECs, signal joint T-cell receptor excision circles; TRECs, T-cell receptor excision circles; CCL2, C-C motif chemokine ligand 2; CCL7, C-C motif chemokine ligand 7; CXCR4, C-X-C chemokine receptor type 4; CXCL9, C-X-C motif chemokine ligand 9; CXCL10, C-X-C motif chemokine ligand 10; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IgM, immunoglobulin M; IgG, immunoglobulin G; Reg3α, regenerating islet derived protein 3 alpha; GM-CSF, granulocyte-macrophage colony-stimulating factor; PDL-1, programmed death-ligand 1; Cox-2, cyclooxygenase-2; NRP-1, neuropilin-1.