HIMF deletion ameliorates acute myocardial ischemic injury by promoting macrophage transformation to reparative subtype

Li, Yanjiao; Dong, Min; Wang, Qing; Kumar, Santosh; Zhang, Rui; Cheng, Wanwen; Xiang, Jiaqing; Wang, Gang; Ouyang, Kunfu; Zhou, Ruxing; Xie, Yaohong; Lu, Yishen; Jing, Y. P.; Duan, Haixia; Liu, Jie

doi:10.1007/s00395-021-00867-7

Cited by 29 publications

(14 citation statements)

References 46 publications

(64 reference statements)

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“…Macrophages as dynamic cells participating in induction and resolution of inflammation [ 2 ] exhibit a significant degree of plasticity and heterogeneity through the function and biology, such as pro-inflammatory M1-like macrophages at one extreme and reparative M2-like macrophages at the other extreme [ 3 , 4 ]. Pro-inflammatory M1-like macrophages strongly express pro-inflammatory cytokines including IL-1β, IL-6 and TNF-α, which initiate the upregulation of destruction mediators in primary tissue and lead to bone resorption [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Exosomes derived from reparative M2-like macrophages prevent bone loss in murine periodontitis models via IL-10 mRNA

et al. 2022

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Background Periodontitis is characterized by progressive inflammation and alveolar bone loss resulting in tooth loss finally. Macrophages including pro-inflammatory M1-like macrophages and reparative M2-like macrophages play a vital role in inflammation and tissue homeostasis in periodontitis. Among them, reparative M2-like macrophages have been shown to promote tissue repair and prevent bone loss. However, the mechanism of reparative M2 macrophages-induced osteoprotective effect remains elusive. Results Exosomes from reparative M2-like macrophages (M2-Exos) were isolated and identified successfully. M2-Exos could promote bone marrow stromal cells (BMSCs) osteogenic differentiation while suppressing bone marrow derived macrophage (BMDM) osteoclast formation, and prohibit pathological alveolar bone resorption because of the intercellular communication via exosomes. High expression level of IL-10 mRNA was detected not only in reparative M2-like macrophages but also in M2-Exos. Meanwhile, IL-10 expression level in BMSCs or BMDM was also upregulated significantly after co-culturing with M2-Exos in a concentration-dependent manner. In vitro, recombinant IL-10 proteins had the ability to selectively promote osteogenic differentiation of BMSCs and hinder osteoclast differentiation of BMDM. Moreover, after treatment with M2-Exos and IL-10R antibody together, the capacity of promoting osteogenesis and suppressing osteoclastogenesis of M2-Exos was significantly reversed. In vivo experiments further showed that M2-Exos reduced alveolar bone resorption in mice with periodontitis via IL-10/IL-10R pathway. Conclusion In conclusion, our results demonstrate that the reparative M2-like macrophages could promote osteogenesis while inhibiting osteoclastogenesis in vitro as well as protect alveolar bone against resorption in vivo significantly. M2-Exos could upregulate the IL-10 cytokines expression of BMSCs and BMDM via delivering exosomal IL-10 mRNA to cells directly, leading to activation of the cellular IL-10/IL-10R pathway to regulate cells differentiation and bone metabolism. These results might partly account for the mechanism of osteoprotective effect of reparative M2-like macrophages and provide a novel perspective and a potential therapeutic approach on improving alveolar resorption by M2-Exos. Graphical Abstract

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Section: Introductionmentioning

confidence: 99%

Exosomes derived from reparative M2-like macrophages prevent bone loss in murine periodontitis models via IL-10 mRNA

et al. 2022

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“…Similarly, HIMF deficiency has also been found to reduce myocardial infarct size and improve cardiac function after MI (Li et al, 2021). HIMF overexpression also directly increased CHOP expression in BMDM and RAW264.7 cells, and regulated macrophage polarization (Li et al, 2021). Taken together, these studies suggest a complex role for HIMF during cardiac injury.…”

Section: Myocardial Infarctionmentioning

confidence: 88%

“…In mice, HIMF deficiency is known to facilitate M2 macrophage transformation and to increase collagen formation and fibrin deposition in the infarct region, preventing the myocardial wall from expansion and rupture. This helps preserve contractility after acute MI (Li et al, 2021). However, HIMF also induces cardiac fibroblast proliferation, migration and differentiation during cardiac hypertrophy and heart failure (Kumar et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…These are contributed by adiponectin-enriched unsorted bone marrow cells (UBCs). Similarly, HIMF deficiency has also been found to reduce myocardial infarct size and improve cardiac function after MI (Li et al, 2021). HIMF overexpression also directly increased CHOP expression in BMDM and RAW264.7 cells, and regulated macrophage polarization (Li et al, 2021).…”

Section: Myocardial Infarctionmentioning

confidence: 97%

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Hypoxia-Induced Mitogenic Factor: A Multifunctional Protein Involved in Health and Disease

Liu

2021

Front. Cell Dev. Biol.

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Hypoxia-induced mitogenic factor (HIMF), also known as resistin-like molecule α (RELMα) or found in inflammatory zone 1 (FIZZ1) is a member of the RELM protein family expressed in mice. It is involved in a plethora of physiological processes, including mitogenesis, angiogenesis, inflammation, and vasoconstriction. HIMF expression can be stimulated under pathological conditions and this plays a critical role in pulmonary, cardiovascular and metabolic disorders. The present review summarizes the molecular characteristics, and the physiological and pathological roles of HIMF in normal and diseased conditions. The potential clinical significance of these findings for human is also discussed.

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“…Smad2/3 siRNA (si.Smad2/3) was purchased from Santa Cruz Biotechnology (Dallas, TX, USA). The siRNAs were transfected with RFect Transfection Reagent (BAIDAI Biotech, Changzhou, China) according to the manufacturer’s instructions 25 . Briefly, to knockdown Smad2 or Smad3 individually or together, GFP-positive primary pericytes were treated with 30 nM siRNA and 0.5% RFect Transfection Reagent for 48 h. The transfection protocol used 30 nM si.Smad2/3 and 0.166% RFect Transfection Reagent in combination with different signaling pathways.…”

Section: Methodsmentioning

confidence: 99%

TGF-β promotes pericyte-myofibroblast transition in subretinal fibrosis through the Smad2/3 and Akt/mTOR pathways

Zhao

Zhang

et al. 2022

Exp Mol Med

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Subretinal fibrosis remains a major obstacle to the management of neovascular age-related macular degeneration. Choroidal pericytes were found to be a significant source of subretinal fibrosis, but the underlying mechanisms of pericyte-myofibroblast transition (PMT) remain largely unknown. The goal of this study was to explore the role and potential mechanisms by which PMT contributes to subretinal fibrosis. Choroidal neovascularization (CNV) was induced by laser photocoagulation in transgenic mice with the collagen1α1-green fluorescent protein (Col1α1-GFP) reporter, and recombinant adeno-associated virus 2 (rAAV2)-mediated TGF-β2 (rAAV2-TGF-β2) was administered intravitreally to further induce PMT. Primary mouse choroidal GFP-positive pericytes were treated with TGF-β2 in combination with siRNAs targeting Smad2/3, the Akt inhibitor MK2206 or the mTOR inhibitor rapamycin to examine cell proliferation, migration, and differentiation into myofibroblasts. The involvement of the Akt/mTOR pathway in PMT in subretinal fibrosis was further investigated in vivo. Intraocular TGF-β2 overexpression induced GFP-positive pericyte infiltration and PMT in subretinal fibrosis, which was mimicked in vitro. Knockdown of Smad2/3 or inhibition of Akt/mTOR decreased cell proliferation, PMT and migration in primary mouse pericytes. Combined inhibition of Smad2/3 and mTOR showed synergistic effects on attenuating α-smooth muscle actin (α-SMA) expression and cell proliferation. In mice with laser-induced CNV, the administration of the Akt/mTOR inhibitors suppressed pericyte proliferation and alleviated the severity of subretinal fibrosis. Our results showed that PMT plays a pivotal role in subretinal fibrosis, which was induced by TGF-β2 through the Smad2/3 and Akt/mTOR pathways. Thus, inhibiting PMT may be a novel strategy for the treatment of subretinal fibrosis.

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HIMF deletion ameliorates acute myocardial ischemic injury by promoting macrophage transformation to reparative subtype

Cited by 29 publications

References 46 publications

Exosomes derived from reparative M2-like macrophages prevent bone loss in murine periodontitis models via IL-10 mRNA

Exosomes derived from reparative M2-like macrophages prevent bone loss in murine periodontitis models via IL-10 mRNA

Hypoxia-Induced Mitogenic Factor: A Multifunctional Protein Involved in Health and Disease

TGF-β promotes pericyte-myofibroblast transition in subretinal fibrosis through the Smad2/3 and Akt/mTOR pathways

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