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 Table of Contents  
Year : 2022  |  Volume : 9  |  Issue : 1  |  Page : 12

Macrophage-myofibroblast transition in kidney disease

Departments of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

Date of Submission27-Jul-2022
Date of Decision21-Sep-2022
Date of Acceptance28-Sep-2022
Date of Web Publication31-Oct-2022

Correspondence Address:
Prof. Hui-Yao Lan
Departments of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2773-0387.358225

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Increasing evidence has shown that immune cell infiltration and activation play a driving role in acute kidney injury (AKI) and chronic kidney disease (CKD) associated with progressive renal fibrosis. Macrophage-myofibroblast transition (MMT) is a newly identified cellular event involved in this process. It is well-recognized that macrophages are a major immune cell that mediates acute renal inflammation, whereas myofibroblasts are an activated form of extracellular matrix (ECM)-producing fibroblasts responsible for tissue repair (wound-healing) or fibrosis under physiological or pathological conditions. A direct link between macrophages and myofibroblasts during the progression from acute to chronic inflammation is lacking. Recent studies have revealed that macrophages play a driving role in acute to chronic inflammation via MMT. Phenotypically, MMT cells exhibit both immune and fibroblast characteristics by co-expressing monocytes/macrophages (CD68 or F4/80) and smooth muscle actin (α-SMA) markers. Moreover, MMT cells are a rich source of myofibroblasts in many chronic inflammatory diseases involving the kidneys, lungs, heart, retina, and tumor microenvironments. Mechanistically, MMT is regulated by many mediators or signaling pathways, specifically the transforming growth factor-beta (TGF-β)/ Smad3 signaling pathway. Research on the mechanisms of MMT and the development of novel therapies targeting MMT for chronic and progressive kidney diseases may present promising opportunities in medicine.

Keywords: Macrophage-myofibroblast transition, acute kidney injury, chronic kidney disease, inflammation, fibrosis

How to cite this article:
Lan HY. Macrophage-myofibroblast transition in kidney disease. Integr Med Nephrol Androl 2022;9:12

How to cite this URL:
Lan HY. Macrophage-myofibroblast transition in kidney disease. Integr Med Nephrol Androl [serial online] 2022 [cited 2023 Jan 28];9:12. Available from: https://journal-imna.com//text.asp?2022/9/1/12/358225

  Introduction Top

Inflammation is regarded as an early process after acute kidney injury (AKI) and is involved in the progression of chronic kidney disease (CKD).[1],[2] Macrophages are key immune cells that play a driving role in the progression from AKI to CKD by inducing acute inflammatory responses while promoting fibrosis.[3],[4] The pathogenic role of macrophages in AKI and CKD has been demonstrated by a number of studies in which phenotypically deleting macrophages or pharmacologically inhibiting macrophage-derived cytokines/chemokines inhibits AKI and CKD.[5],[6],[7],[8] Myofibroblasts are activated fibroblasts that co-express alpha-smooth muscle actin (α-SMA) and other markers including collagens, vimentin, platelet-derived growth factor receptor-β (PDGFR-β), fibroblast-specific protein 1 (FSP-1), and CD73.[7] Many studies have identified α-SMA+ myofibroblasts as a major cell type that leads to CKD with progressive renal fibrosis. It has been suggested that myofibroblasts are derived from several cellular events, including tubular epithelial-mesenchymal transition (EMT), endothelial-mesenchymal transition (EndMT), resident renal fibroblast proliferation, pericyte activation and differentiation, and bone marrow-derived fibrocytes.[3] However, the origin of myofibroblasts during renal fibrosis remains controversial and has been debated in recent decades.[8] The importance of myofibroblasts in renal fibrosis has been demonstrated in Pdgfrb-Cre and aSMA-tk mice, where conditional ablation of myofibroblasts attenuated progressive renal fibrosis by reducing α-SMA+ myofibroblasts by 50 % in a mouse model of unilateral ureteral obstructive nephropathy (UUO).[9] Although both macrophages and myofibroblasts are abundant in CKD, direct evidence supporting an association between macrophages and myofibroblasts during the progression from AKI to CKD remains controversial. Moreover, the identification of the myofibroblast origin during the progression of inflammatory kidney diseases with active fibrosis remains challenging.

A breakthrough finding from our recent studies suggests that inflammatory macrophages can transform into collagen- producing myofibroblasts directly via the process of macrophage- myofibroblast transition (MMT).[10],[11],[12] MMT is a rich source of myofibroblasts in diseased kidneys with active inflammation and fibrosis, which contributes significantly to the progressive renal fibrosis in both CKD patients and animal models.[10],[11],[12],[13],[14],[15],[16] MMT is also common in other chronic diseases involving the lungs, heart, retina, and tumor microenvironment.[17],[18],[19],[20],[21],[22],[23],[24],[25] Thus, the identification of MMT and its mechanisms, and the development of new therapeutic strategies for CKD by specifically targeting MMT, may represent new and promising opportunities in the field of nephrology.

  Identification of MMT Top

MMT cells have both macrophage and myofibroblast phenotypes and can be detected locally by two-color immunohistochemistry and quantitatively by flow cytometry with their unique co-expression of macrophage (CD68) and myofibroblast (a-SMA) markers in the diseased kidney.[10],[11],[12] In addition, MMT cells can also be recognized at the single-cell level by in situ Z-stake imaging, in which CD68 (or F4/80)+ α-SMA+ MMT cells can be clearly identified and distinguished from twisted macrophages and myofibroblasts.[10],[11],[12] Specifically, MMT cells can be uncovered using advanced single-cell RNA sequencing (scRNA-seq). Using this technique, the number of MMT cells can be precisely and quantitatively detected by the co- expression of CD68 or the transcription factor MAFB of macrophages and ACTA2 (myofibroblast gene marker).[17] Furthermore, under the MMT process, macrophages can be detected using lineage-tracing or fate-mapping technologies in which macrophage-expressing tracing markers, such as GFP or tomato, during their differentiation, activation, and MMT process, can be clearly identified in vivo and in virro.[10],[11],[12]

  MMT in Kidney Diseases Top

As MMT cells co-express both macrophage and myofibroblast markers, MMT cells can be regarded as pro-inflammatory fibroblasts and pro-fibrotic macrophages that play an active role in inflammation and fibrosis. In CKD patients with active renal inflammation and fibrosis, including crescentic glomerulonephritis, IgA nephropathy, and chronic renal allograft rejection, CD68+α-SMA+ MMT cells are abundantly found and are a major source of myofibroblasts, accounting for up to 80% of the α-SMA+ cells.[11],[12] In contrast, few MMT cells are detectable in patients with minimal changes in kidney disease and inactive chronic rejection.[11],[12] Importantly, we also found that CD68+α-SMA+ MMT cells, but not α-SMA+ myofibroblasts, were closely correlated with progressive renal dysfunction in kidneys with active chronic allograft rejection.[12] Thus, MMT cells may function as pro-inflammatory fibroblasts and pro-fibrotic macrophages, causing progressive renal inflammation and fibrosis. MMT is also common in animal models of CKD, including unilateral ureteral obstructive (UUO) nephropathy,[10],[11],[16] chronic allograft rejection,[12] ischemic reperfusion injury,[13] and diabetic nephropathy,[14] and obstructive sleep apnoea syndrome.[15] Lineage-tracing studies using GFP chimeric mice and LysM-Cre/Rosa26-tdTomato mice revealed that the majority of MMT cells (> 80%) are derived from bone marrow macrophages, identified as GFP+/Tomato+F4/80+a-SMA+ cells.[11],[12] This may also account for the previous finding that bone-marrow-derived fibroblasts contribute to renal fibrosis as reported in mouse models.[26],[27],[28] Thus, these bone marrow- derived fibrogenic cells contribute to the development of progressive renal inflammation and fibrosis in mouse models of UUO,[10],[11],[16] diabetic nephropathy,[14] and chronic allograft rejection.[12] Adoptive transfer of GFP+F4/80+ bone marrow macrophages into irradiated UUO mice gives rise to GFP+F4/80+a-SMA+ myofibroblasts and progressive renal fibrosis.[11] These findings suggest a driving role of MMT in the pathogenesis of renal inflammation and fibrosis.

  MMT in Other Diseases Top

MMT has also been reported in many other chronic diseases involving the lungs, heart, liver, retina, and in cancers.[17],[18],[19],[20],[21],[22],[23],[24],[25] Using scRNA-seq, approximately half (50%–60%) of the myofibroblasts are identified as MMT cells. MMT cells are identified by the co-expressing ACTA2 (a-SMA gene) and CD68 in patients with idiopathic pulmonary fibrosis (IPF) and in experimental mouse model of cancer in which transition of tumour-associated macrophages to cancer-associated fibroblast contributes significantly to cancer invasion.[17],[24]

Using the macrophage differentiation factor, MafB, one-third of the MMT cells in IPF lung tissues have also demonstrated the co-expression of ACTA2 and MafB gene markers.[17] This is also observed in UUO-induced pulmonary fibrosis, where approximately 30% of myofibroblasts are derived from MMT.[18] Furthermore, MMT is also involved in myocardial remodeling and contributes to subretinal fibrosis.[21],[22],[23] Of note, our recent study has shown that MMT is a major source of cancer-associated fibroblasts that play a critical role in cancer progression.[24],[25]

  Regulatory Mechanisms of MMT Top

TGF-b has been recognized as a master regulator during renal fibrosis.[29],[30] MMT is regulated by the transforming growth factor-beta 1 (TGF-β1)/Smad3 signaling pathway.[6],[7] This is evident from studies in which mice lacking Smad3 are protected from UUO or renal graft-induced MMT and progressive renal fibrosis.[10],[12] This has also been confirmed in vitro in bone marrow-derived macrophages (BMDMs), in which Smad3 deficiency protected against TGF-β1-induced MMT and collagen matrix production.[10],[12] Using scRNA-seq, we uncovered that the Smad3-Src-Pou4f1 pathway is a key regulatory network in MMT.[31],[32] Using chromatin immunoprecipitation (ChIP) and reporter assays, we found Smad3 binding to Scr and Pou4, thereby, enhancing their promoter activity during the MMT process.[31],[32] It has been well documented that the Src kinase plays a critical role in renal fibrosis by integrating multiple fibrogenic signals and targeted inhibition of Src kinase can block renal fibrosis under high TGF-β conditions.[33] Pou4F1 is a member of the POU-IV class of neural transcription factors. We found that Pou4f1 is the only transcription factor involved in TGF-β1/Smad3-mediated MMT based on an unbiased gene network analysis.[32] Pou4f1 is highly expressed by macrophages undergoing MMT in the fibrotic tissues of human and experimental kidney diseases.[32] Like Smad3 deficient mice, treatment of UUO mice or BMDMs with an Src inhibitor or by silencing Pou4f1 revealed an essential role for the Smad3-Src-Pou4f1 pathway in MMT and renal fibrosis.[31],[32],[33] It is reported that MMT can aso be inducedvia the GSDMD-dependent neutrophil extracellular traps-dependent mechanism.[16] The fatty acid-binding protein 4 (FABP4) is also responsible for MMT.[34] Aldosterone stimulates MMT and renal fibrosis via the mineralocorticoid receptor under hypoxic conditions.[35],[36],[37] Interestingly, our recent study also revealed that P2Y12 expression is induced by TGF-β1 and can promote MMT via the Smad3-dependent mechanism.[38] Thus, MMT may be regulated by different mechanisms under various disease conditions.

  MMT as A Therapeutic Target for Kidney Disease Top

MMT is a key cellular event that drives kidney disease progression from AKI to CKD and is regulated by the Smad3-Src-Pou4f1 gene network, as well as FABP4, MR, and P2Y12. Treatment with inhibitors of Smad3, Src, FABP4, MR, or P2Y12 has been shown to inhibit MMT-associated renal fibrosis.[10],[11],[12],[31],[32],[33],[34],[35],[36],[37],[38] Thus, targeting bone-marrow-derived MMT pathway may represent as a promising approach for treatment of renal fibrosis.[39],[40] However, the specificity of these therapeutic strategies remains unclear. Furthermore, the results from these studies are preliminary and largely based on experimental observations. The translation of such experimental findings to clinical practice in human diseases and the development of more specific and effective anti-MMT treatment strategies for CKD remains challenging.

  Conclusion Top

In summary, as outlined in [Figure 1], MMT is a rich source of myofibroblasts and plays a driving role in the transition from AKI to CKD. MMT is regulated by TGF-β1 via the Smad3-Src-Pou4f1 pathway. Targeting this pathway may offer a novel and specific therapeutic approach for combating MMT and tissue fibrosis. Thus, research on MMT may present promising opportunities for immune and inflammatory diseases with progressive tissue fibrosis.
Figure 1: TGF-β1 induces MMT and renal fibrosis via the Smad3-Src-Pou4f1 pathway, which can be blocked by inhibitors to Smad3, Src, or Pou4f1. MMT, macrophage-myofibroblast transition; AKI, acute kidney injury; CKD, chronic kidney disease; TGF-β1, transforming growth factor-beta 1; ECM, extracellular matrix.

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Financial support and sponsorship

This work was supported by the Research Grants Council of Hong Kong (14117418, 14104019, and 14101121), Lui Che Woo Institute of Innovative Medicine (CARE Program), and the Guangdong-Hong Kong-Macao-Joint Labs Program from Guangdong Science and Technology (2019B121205005).

Conflicts of interest

Hui-Yao Lan is a Co-Editor-in-Chief of the journal. The article was subject to the journal’s standard procedures, and peer review was handled independently of this editor and his research groups.

  References Top

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