Mesenchymal stem cells as a therapeutic tool to treat sepsis

Table 1 Efficacy preclinical studies on experimental models of sepsis using mesenchymal stem cells, mesenchymal stem cell-conditioned medium or mesenchymal stem cell-derived macrophages

Animal model	MSC type	Route/time	Dose	Number of doses	Therapeutic effects					MoA	Ref.
					Survival	Cytokines	Inflammatory infiltration	Organ injury	Bacterial load
LPS, mouse	hASCs (xeno)	I.P/after 0.5 h or I.P/after 0.5 h	3 × 105 106	1 1	Improved Improved	Reduced pro-inflammatory cytokines in serum, liver, lung and intestine Increased anti-inflammatory cytokine (IL10) in liver, lung and intestine	Reduced lymphocyte, neutrophil and macrophage infiltration in peritoneum, liver, lung and intestine	ND	ND	ND	Gonzalez-Rey et al[52]
LPS, mouse	hBM-MSCs (xeno) normal/senescent	I.P/after 0.5 h	106	1	Improved only by normal cells	Reduced pro-inflammatory cytokines in serum and lungs (normal cells) Reduced anti-inflammatory cytokine (IL10) in serum (normal cells)	ND	ND	ND	ND	Sepúlveda et al[67]
LPS, mouse	hASC/BM-MSC-CM	I.P/at 0 h	1 mL CM (from 2× 106 cells per milliliter)	1	Improved only by hBM-MSC CM	ND	Reduced neutrophil infiltration in kidney (hBM-MSC CM)	Improved kidney, liver and lung damage (hBM-MSC CM)	ND	ND	Elman et al[65]
LPS, rat	hASCs (xeno)	I.V/after 0.5 h	2 × 106	1	ND	Reduced pro-inflammatory cytokines in lung No effect on anti-inflammatory cytokine (IL10)	ND	Improved kidney, liver and lung damage	ND	ND	Shin et al[75]
LPS, rat	hBM-MSCs (xeno)	I.M/at 0 h	2 × 106	1	ND	ND	ND	Improved kidney, liver and lung damage	ND	ND	Yagi et al[73]
LPS, rat	hBM-MSCs (xeno)	I.M/at 0 h	2 × 106	1	ND	Reduced pro-inflammatory cytokines in serum	Reduced neutrophil and macrophage infiltration in kidney, liver and lung	ND	ND	MSC release of sTNFR1	Yagi et al[76]
LPS, rat	mBM-MSCs (xeno)	I.P/after 1 h	2 × 106	1	ND	Reduced pro-inflammatory cytokines in serum and myocardium Increased anti-inflammatory cytokine (IL10) in serum but not in myocardium	ND	Improved myocardial damage Cells from female donors showed higher effect	ND	Higher expression of anti-apoptotic proteins in myocardium	Manukyan et al[71]
LPS, rat	mBM-MSCs (xeno)	I.P/after 1 h	2 × 106	1	ND	Reduced pro-inflammatory cytokines in serum and myocardium Increased anti-inflammatory cytokine (IL10) in serum but not in myocardium	ND	Improved myocardial damage	ND	ND	Weil et al[72]
LPS, rat	rBM-MSCs (auto)	I.V/after 1 h	2.5 × 106	1	ND	Reduced pro-inflammatory cytokines in serum and myocardium Increased anti-inflammatory cytokine (IL10) in serum but not in myocardium	ND	Improved myocardial damage	ND	ND	Weil et al[74]
CLP, mouse	hASCs (xeno) mASCs (auto/allo)	I.P/after 4 h	106	1	Improved	Reduced pro-inflammatory cytokines in serum, liver, lung and intestine Increased anti-inflammatory cytokine (IL10) in liver, lung and intestine	Reduced lymphocyte, neutrophil and macrophage infiltration in peritoneum, liver, lung and intestine	ND	ND	ND	Gonzalez-Rey et al[52]
CLP, mouse	mBM-MSCs (auto/allo)	I.V/24 h prior or I.V/after 1 h	106 106	1 1	Improved Improved	Reduced pro-inflammatory cytokines in serum Increased anti.inflammatory cytokine (IL10) in serum	Reduced neutrophil infiltration in peritoneum, liver and kidney	Improved kidney, liver, pancreatic and spleen damage and vascular permeability	Reduced bacterial counts in blood	Anti-inflammatory Mph (IL10) induced by MSCs through PGE2	Németh et al[61]
CLP, mouse	mBM-MSCs (auto)	I.V/after 6 h	2.5 × 105	1	Improved	Reduced pro-inflammatory cytokines in serum and BAL No effect on anti.inflammatory cytokine (IL10) in serum and BAL	Reduced neutrophil infiltration in peritoneum, liver and kidney	Improved kidney and lung damage. No effect on liver and pancreatic damage	Reduced bacterial counts in spleen	Increased phagocytic activity of macrophages and neutrophils	Mei et al[62]
CLP, mouse	mBM-MSCs (auto)	I.V/after 2 h and I.V/after 24 h and I.V/after 48 h	5 × 105 2.5 × 105 2.5 × 105 total: 106	3	Improved	ND	Reduced neutrophil infiltration in bowel	Improved bowel, kidney, liver and spleen damage	Reduced bacterial counts in peritoneum and blood	Increased phagocytic activity of neutrophils	Hall et al[64]
CLP, mouse	mBM-MSCs (auto)	I.V/after 3 h	106	1	Improved	Reduced pro-inflammatory cytokines in serum Increased anti-inflammatory cytokine (IL10) in serum	Reduced neutrophil infiltration in kidney	Improved kidney damage	Reduced bacterial counts in blood	ND	Luo et al[66]
CLP, mouse	ASC-derived mouse Mph	I.P/after 4 h or I.P/after 6 h or I.P/after 12 h or I.P/after 24 h	106 106 106 106	1 1 1 1	Improved Improved Improved No effect	Reduced pro-inflammatory cytokines in serum (only treatment at 4 h tested)	Reduced lymphocyte, neutrophil and macrophage infiltration in peritoneum, lung, liver and intestine (only treatment at 4 h tested)	ND	ND	IL10 secreted by Mph	Anderson et al[77]
CLP, mouse	hUC-MSCs (xeno) wt/Poly I:C preactivated	I.V/after 1 h	106	1	Improved Better preactivated	Reduced pro-inflammatory cytokines in plasma Better preactivated	Reduced inflammatory infiltration in kidney, liver and lung	Improved kidney, liver and pancreatic damage Better preactivated	Reduced bacterial counts in peritoneum and blood Better preactivated	Poly I:C inhibition of MiR-143 expression by MSCs	Zhao et al[68]
CLP, rat	rASCs (auto) living/apoptotic	I.P/after 0.5 h and I.P/after 6 h and I.P/after 18 h	1.2 × 106 1.2 × 106 1.2 × 106 total: 3.6 ×106	3	Higher mortality by living cells Improved by apoptotic cells	Reduced TNFα ( apoptotic rASC treated rats)	ND	Improved kidney, liver, lung and myocardial damage (apoptotic rASCs)	ND	ND	Chang et al[69]
E.coli pneumonia, mouse	hBM-MSCs (xeno)	I.T/after 4 h	106	1	ND	Reduced pro-inflammatory cytokines in bronchoalveolar liquid (BAL)	Reduced neutrophil infiltration in BAL	Improved lung epithelial and endothelial permeability	Reduced bacterial counts in BAL	MSC release of the antimicrobial peptide LL-37	Krasnodems- kaya et al[70]
P. aeruginosa peritonitis, mouse	hBM-MSCs (xeno)	I.V/after 1 h	106	1	Improved	No changes in serum or peritoneal fluid levels of pro or anti-inflammatory mediators	ND	ND	Reduced bacterial counts in peripheral blood, peritoneal fluid, lung, and spleen	Increased phagocytic activity of macrophages Generation of anti-inflammatory macrophages in spleen	Krasnodems- kaya et al[63]

LPS: Lipopolysaccharide; CLP: Caecal ligation and puncture; h: Human; r: Rat; m: Mouse; ASCs: Adipose mesenchymal stem cells; BM-MSCs: Bone marrow mesenchymal stem cells; UC-MSCs: Umbilical cord mesenchymal stem cells; Mph: Macrophages; I.P: Intraperitoneal; I.V: Intravenous; I.T: Intratracheal; I.M: Intramuscular; ND: Not determined; CM: Conditioned medium.