Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies,despite uncertainty about its clinical therapeutic effcacy and unclear underlying mechanisms.Here,w...Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies,despite uncertainty about its clinical therapeutic effcacy and unclear underlying mechanisms.Here,we investigated the role of follistatinlike 1(FsTL1),a profibrotic and proinflammatory matricellular protein,in inflammation-related heterogeneity in stem cell therapy.Our results showed that a high level of circulating FSTL1 is significantly correlated with therapeutic response in patients with cirrhosis.FSTL1 facilitated MSC^(-)mediated early recruitment of Ly6C^(+)inflammatory macrophages within 24 h postinfusion,which Was essential for the empowerment of MSCs and subsequent Ly6C^(-)CX3CR1^(+)macrophage remodelling at 48 h postinfusion.Fstl1 deficiency abrogated early macrophage recruitment and effective Ly6C^(-)CX3CR1^(+)macrophage accumulation,resulting in the poor antifibrotic effect of MSCs in mice.Whereas,recombinant FSTL1 protein restored the therapeutic efficacy of MSCs in CCl_(4)-injured Fstl1^(+/-)mice.Mechanistically,host FSTL1 enhanced rapid recycling of CCR2 to the membrane via activation of the CD14/TLR4/NFkB/ATP6V1G2 axis,leading to early recruitment of Ly6C^(+)monocytes/macrophages.Taken together,our findings revealed that FSTL1 is a critical regulator of the fibrotic immune microenvironment and facilitates subsequent stem cell therapy.These data suggest that FSTL1 could serve as a predictive biomarker of stem cell therapy response in patients with liver cirrhosis.展开更多
基金supported by the National Key R&D Program of China 2020YFA0710803(to J.W.),2017YFA0105704(to Y.H.),2021YFC25007002024YFA1108500(to W.N.)+1 种基金the National Natural Science Foundation of China(NSFC)grants 81900570,82470638(to X.Z.),82270551(to Y.H.),82270616(to J.W.),81900502(to G.G.),82303155(T.L.),82372882(L.G.)and 82030001(to W.N.)the Key Research and Development Program of Shaanxi Province,China no.2021ZDLSF02-07(toY.H.).
文摘Adult stem cell therapy holds great promise for treating decompensated liver cirrhosis on the basis of animal studies,despite uncertainty about its clinical therapeutic effcacy and unclear underlying mechanisms.Here,we investigated the role of follistatinlike 1(FsTL1),a profibrotic and proinflammatory matricellular protein,in inflammation-related heterogeneity in stem cell therapy.Our results showed that a high level of circulating FSTL1 is significantly correlated with therapeutic response in patients with cirrhosis.FSTL1 facilitated MSC^(-)mediated early recruitment of Ly6C^(+)inflammatory macrophages within 24 h postinfusion,which Was essential for the empowerment of MSCs and subsequent Ly6C^(-)CX3CR1^(+)macrophage remodelling at 48 h postinfusion.Fstl1 deficiency abrogated early macrophage recruitment and effective Ly6C^(-)CX3CR1^(+)macrophage accumulation,resulting in the poor antifibrotic effect of MSCs in mice.Whereas,recombinant FSTL1 protein restored the therapeutic efficacy of MSCs in CCl_(4)-injured Fstl1^(+/-)mice.Mechanistically,host FSTL1 enhanced rapid recycling of CCR2 to the membrane via activation of the CD14/TLR4/NFkB/ATP6V1G2 axis,leading to early recruitment of Ly6C^(+)monocytes/macrophages.Taken together,our findings revealed that FSTL1 is a critical regulator of the fibrotic immune microenvironment and facilitates subsequent stem cell therapy.These data suggest that FSTL1 could serve as a predictive biomarker of stem cell therapy response in patients with liver cirrhosis.
