INT-HA induces M2-like macrophage differentiation of human monocytes via TLR4-miR-935 pathway

Zhang, Boke; Du, Yan; Liu, Yiwen; Zhang, Guoliang; Yang, Cuixia; Gao, Feng

doi:10.1007/s00262-018-2261-6

Cited by 31 publications

(24 citation statements)

References 38 publications

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“…Additionally, HA appears to have a modulatory effect on immune cells 43, 44, 64. HA interaction with TLR4 can educate macrophage polarization to an M2-like phenotype 65. HA was synthesized and released from HUMSCs in vitro in this study (Figure 9A).…”

Section: Discussionmentioning

confidence: 67%

Reversal of bleomycin-induced rat pulmonary fibrosis by a xenograft of human umbilical mesenchymal stem cells from Wharton's jelly

Chu¹,

Wang²,

Yeh³

et al. 2019

Theranostics

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Pulmonary fibrosis (PF) is a progressive and irreversible condition with various causes, and no effective treatment has been found to rescue fibrotic lungs. Successful recovery from PF requires inhibiting inflammation, promoting collagen degradation and stimulating alveolar regeneration. Human umbilical mesenchymal stem cells (HUMSCs) not only regulate immune responses but also synthesize and release hyaluronan to improve lung regeneration. This study investigated the feasibility of HUMSC engraftment into rats with bleomycin (BLM)-induced PF to explore HUMSC therapeutic effects/outcomes.Methods: A unique BLM-induced left-lung-dominated PF animal model was established. Rats were transplanted with low-dose (5×106) or high-dose (2.5×107) HUMSCs on Day 21 after BLM injection. Combinations in co-culture of pulmonary macrophages, fibroblasts, HUMSCs treated with BLM and the same conditions on alveolar epithelia versus HUMSCs were evaluated.Results: Rats with high-dose HUMSC engraftment displayed significant recovery, including improved blood oxygen saturation levels and respiratory rates. High-dose HUMSC transplantation reversed alveolar injury, reduced cell infiltration and ameliorated collagen deposition. One month posttransplantation, HUMSCs in the rats' lungs remained viable and secreted cytokines without differentiating into alveolar or vascular epithelial cells. Moreover, HUMSCs decreased epithelial-mesenchymal transition in pulmonary inflammation, enhanced macrophage matrix-metallopeptidase-9 (MMP-9) expression for collagen degradation, and promoted toll-like receptor-4 (TLR-4) expression in the lung for alveolar regeneration. In coculture studies, HUMSCs elevated the MMP-9 level in pulmonary macrophages, released hyaluronan into the medium and stimulated the TLR-4 quantity in the alveolar epithelium.Principal Conclusions: Transplanted HUMSCs exhibit long-term viability in rat lungs and can effectively reverse rat PF.

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Section: Discussionmentioning

confidence: 67%

Reversal of bleomycin-induced rat pulmonary fibrosis by a xenograft of human umbilical mesenchymal stem cells from Wharton's jelly

Chu¹,

Wang²,

Yeh³

et al. 2019

Theranostics

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“…A TLR9/IL-6/JAK/STAT3 pathway in tumor-associated myeloid cells plays an essential role in initiating the cancer recurrence after radiotherapy 36 . The tumor-derived intermediate-sized hyaluronan fragments have been recently reported to induce M2 macrophage polarization via the TLR4/mir-935 pathway to promote tumor progression 37 . A lung cancer-derived extracellular-matrix protein versican is reported to cause a TLR2-dependent activation and M2-phenotype polarization in TAM to induce tumor metastasis 38 .…”

Section: Discussionmentioning

confidence: 99%

Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis

Shiau

Kuo

Davuluri

et al. 2020

Sci Rep

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In many human cancers, including hepatocellular carcinoma (HCC), high density of infiltrating tumor-associated macrophages (TAM) is associated with poor prognosis. Most TAMs express a M2 phenotype subsequently supporting tumor growth. How tumor cells polarize these TAMs to a pro-tumor M2 phenotype is still poorly understood. Our previous studies have revealed that a Toll-like receptor 2 (TLR2)-dependent autophagy triggered by hepatoma-derived factors down-regulates NF-κB p65 and drives M2 macrophage differentiation. However, the underlying mechanisms and potential hepatoma-derived TLR2 ligands are not clear. Here, we provide evidence to reveal that NADPH oxidase 2 (NOX2)-dependent reactive oxygen species (ROS) generation is crucial for HCC-induced autophagy, NF-κB p65 down-regulation and M2 phenotype polarization in primary macrophages. This NOX2-generated ROS production in abolished in TLR2-deficient macrophages. HCC-derived or recombinant high-mobility group box 1 (HMGB1) is able to trigger this TLR2-mediated M2 macrophage polarization. Blockage of HMGB1 and ROS by inhibitors, ethyl pyruvate and N-acetylcysteine amide, respectively, significantly reduces both M2 macrophage accumulation and liver nodule formation in HCC-bearing mice. Our findings uncover a HMGB1/TLR2/NOX2/autophagy axis to trigger M2 macrophage polarization in HCC that can be considered as a novel therapeutic target for treating HCC.

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“…Activation of TLR-4 plays a vital role in the regeneration and reconstitution of alveolar epithelial cells [37,38]. Furthermore, the binding of hyaluronan and TLR-4 could also promote macrophage to differentiate into M2 phenotypes [39]. We previously discovered that the transplantation of HUMSCs robustly increased the TLR-4 protein around the alveolar circumference and in the M2 macrophage [9].…”

Section: Discussionmentioning

confidence: 99%

Comparison of reversal of rat pulmonary fibrosis of nintedanib, pirfenidone, and human umbilical mesenchymal stem cells from Wharton’s jelly

Chu

Yeh

Kuo³

et al. 2020

Stem Cell Res Ther

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Background The present study compared the effects of antifibrotic medications, pirfenidone, and nintedanib, with transplantation of human umbilical mesenchymal stem cells (HUMSCs) in restoring rat pulmonary fibrosis (PF). Methods A stable animal model was established via an intratracheal injection of 5 mg bleomycin (BLM). One single transplantation of 2.5× 107 HUMSCs or initiation of daily oral nintedanib/pirfenidone administration was performed on day 21 following BLM damage. Results Pulmonary function examination revealed that BLM rats exhibited a significant decrease in blood oxygen saturation and an increase in respiratory rates. While no significant improvements were found in BLM rats receiving nintedanib or pirfenidone, those who transplanted with HUMSCs showed a statistical amelioration in blood oxygen saturation and significant alleviation in respiratory rates. Quantification results revealed that a significant reduction in alveolar space and marked increases in substantial cell infiltration and collagen deposition in the left lungs of BLM rats. No significant alteration was observed in BLM rats administered nintedanib or pirfenidone. However, BLM rats transplanted with HUMSCs had a significant recovery in alveolar space and noticeable decreases in cell infiltration and collagen deposition. The inflammatory cell numbers in the bronchoalveolar lavage was increased in the BLM group. While the rats treated with nintedanib or pirfenidone had a lower cell number than the BLM group, a higher cell number was found as compared with the Normal group. In rats transplanted with HUMSCs, the cell number did not differ from the Normal group. Conclusions Transplantation of HUMSCs could effectively treat PF as opposed to the administration of anti-fibrotic drugs with nintedanib or pirfenidone with a significant better result in lung volume, pathological changes, lung function, and blood oxygen saturation.

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INT-HA induces M2-like macrophage differentiation of human monocytes via TLR4-miR-935 pathway

Cited by 31 publications

References 38 publications

Reversal of bleomycin-induced rat pulmonary fibrosis by a xenograft of human umbilical mesenchymal stem cells from Wharton's jelly

Reversal of bleomycin-induced rat pulmonary fibrosis by a xenograft of human umbilical mesenchymal stem cells from Wharton's jelly

Hepatocellular carcinoma-derived high mobility group box 1 triggers M2 macrophage polarization via a TLR2/NOX2/autophagy axis

Comparison of reversal of rat pulmonary fibrosis of nintedanib, pirfenidone, and human umbilical mesenchymal stem cells from Wharton’s jelly

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