Complement C1q Activates Canonical Wnt Signaling and Promotes Aging-Related Phenotypes

Naito, Atsuhiko T.; Sumida, Tomokazu; Nomura, Seitaro; Liu, Mei‐Lan; Higo, Tomoaki; Nakagawa, Akito; Okada, Katsuki; Sakai, Taku; Hashimoto, Akihito; Hara, Yurina; Shimizu, Ippei; Zhu, Weidong; Toko, Haruhiro; Katada, Akemi; Akazawa, Hiroshi; Oka, Tôru; Lee, Jong-Kook; Minamino, Tetsuo; Nagai, Takeharu; Walsh, Kenneth; Kikuchi, Akira; Matsumoto, Misako; Botto, Marina; Shiojima, Ichiro; Komuro, Issei

doi:10.1016/j.cell.2012.07.014

Cited by 32 publications

(44 citation statements)

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“…The effect is generally considered a host defense mechanism for eliminating pathogen-infected cells. Interestingly, the concentration of C1q in serum and its expression levels in various tissues were found to be elevated during the aging process, possibly as a mechanism to activate the β-catenin pathway in aging cells (22). Our present study shows that this mechanism works to regulate the expansion and dedifferentiation of HPCs in the senescence-associated inflammatory liver.…”

Section: Discussionsupporting

confidence: 50%

“…In addition to C1q's function as the initiator for the classical complement system (21), a recent study identified a novel function of C1q in the activation of the canonical Wnt pathway by binding to Frizzled receptors to activate C1r and C1s, which cleaves the ectodomain of LRP6 to trigger the β-catenin pathway (22). A positive signal for GS, a target gene for the β-catenin pathway in liver, supports activation of the β-catenin pathway, a major factor responsible for the proliferation and stemness of progenitor cells (23), in the expanding periportal HPCs ( Fig.…”

Section: Complement C1q Is Elevated In the Inflammatory Niche As A Camentioning

confidence: 99%

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Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver

Wang

Yeh

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Most hepatocellular carcinomas (HCCs) develop in patients with chronic hepatitis, which creates a microenvironment for the growth of hepatic progenitor cells (HPCs) at the periportal area and subsequent development of HCCs. We investigated the signal from the inflammatory liver for this pathogenic process in the hepatic conditional β-catenin knockout mouse model. Senescent β-catenin–depleted hepatocytes in aged mice create an inflammatory microenvironment that stimulates periportal HPC expansion but arrests differentiation, which predisposes mice to the development of liver tumors. The release of complement C1q from macrophages in the inflammatory niche was identified as the unorthodox signal that activated the β-catenin pathway in periportal HPCs and was responsible for their expansion and de-differentiation. C1q inhibitors blocked the β-catenin pathway in both the expanding HPCs and the liver tumors but spared its orthodox pathway in pericentral normal hepatocytes. This mechanism has been validated in human liver specimens from patients with chronic hepatitis. Taken together, these results demonstrate that C1q- mediated activation of β-catenin pathway in periportal HPCs is a previously unrecognized mechanism for replenishing hepatocytes in the inflammatory liver and, if unchecked, for promoting hepatocarcinogenesis. C1q may become a new target for blocking carcinogenesis in patients with chronic hepatitis.

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Section: Discussionsupporting

confidence: 50%

Section: Complement C1q Is Elevated In the Inflammatory Niche As A Camentioning

confidence: 99%

Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver

Wang

Yeh

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…This leads to generation of the C3 convertase C4bC2a, which activates C3 and initiates the lytic pathway . Recent observations on the diversity of C1q ligands and C1s substrates suggest that C1 has functions outside the complement system …”

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confidence: 99%

Tumour‐cell‐derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma

et al. 2019

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Summary Background The incidence of epidermal keratinocyte‐derived cutaneous squamous cell carcinoma (cSCC) is increasing worldwide. Objectives To study the role of the complement classical pathway components C1q, C1r and C1s in the progression of cSCC. Methods The mRNA levels of C1Q subunits and C1R and C1S in cSCC cell lines, normal human epidermal keratinocytes, cSCC tumours in vivo and normal skin were analysed with quantitative real‐time polymerase chain reaction. The production of C1r and C1s was determined with Western blotting. The expression of C1r and C1s in tissue samples in vivo was analysed with immunohistochemistry and further investigated in human cSCC xenografts by knocking down C1r and C1s. Results Significantly elevated C1R and C1S mRNA levels and production of C1r and C1s were detected in cSCC cells, compared with normal human epidermal keratinocytes. The mRNA levels of C1R and C1S were markedly elevated in cSCC tumours in vivo compared with normal skin. Abundant expression of C1r and C1s by tumour cells was detected in invasive sporadic cSCCs and recessive dystrophic epidermolysis bullosa‐associated cSCCs, whereas the expression of C1r and C1s was lower in cSCC in situ, actinic keratosis and normal skin. Knockdown of C1r and C1s expression in cSCC cells inhibited activation of extracellular signal‐related kinase 1/2 and Akt, promoted apoptosis of cSCC cells and significantly suppressed growth and vascularization of human cSCC xenograft tumours in vivo. Conclusions These results provide evidence for the role of tumour‐cell‐derived C1r and C1s in the progression of cSCC and identify them as biomarkers and putative therapeutic targets in cSCC. What's already known about this topic? The incidences of actinic keratosis, cutaneous squamous cell carcinoma (cSCC) in situ and invasive cSCC are increasing globally. Few specific biomarkers for progression of cSCC have been identified, and no biological markers are in clinical use to predict the aggressiveness of actinic keratosis, cSCC in situ and invasive cSCC. What does this study add? Our results provide novel evidence for the role of complement classical pathway components C1r and C1s in the progression of cSCC. What is the translational message? Our results identify complement classical pathway components C1r and C1s as biomarkers and putative therapeutic targets in cSCC.

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“…The induction of a basal inflammatory context is also reflected in the upregulation of multiple components of the complement system, which so far had been associated to HSPC mobilization to peripheral tissues during stress hematopoiesis (Ratajczak et al, 2010). Overexpression of complement genes is a hallmark of aging tissues and abnormal activation of this system has been linked to the emergence of degenerative diseases and cancer (de Magalhães et al, 2009;McGeer et al, 2005;Naito et al, 2012). Thus, it will be crucial to understand to what extent complement components and cytokines identified here contribute to the selective pressure that results in aging-induced clonality and increased incidence of hematologic neoplasia (Henry et al, 2015;Cooper and Young, 2017).…”

Section: Discussionmentioning

confidence: 99%

Global Transcriptomic Profiling of the Bone Marrow Stromal Microenvironment During Postnatal Development, Aging and Inflammation

et al. 2019

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Bone marrow (BM) stromal cells provide the regulatory framework for hematopoiesis and contribute to developmental stage-specific niches, such as those preserving hematopoietic stem cells. Despite advances in our understanding of stromal function, little is known about the transcriptional changes that this compartment undergoes throughout lifespan and during adaptation to stress. Using RNA sequencing, we perform transcriptional analyses of four principal stromal subsets, namely CXCL12-abundant reticular, platelet-derived growth factor receptor (PDGFR)-+ Sca1 + , sinusoidal, and arterial endothelial cells, from early postnatal, adult, and aged mice. Our data reveal (1) molecular fingerprints defining cellspecific anatomical and functional features, (2) a radical reprogramming of pro-hematopoietic, immune, and matrisomic transcriptional programs during the transition from juvenile stages to adulthood, and (3) the aging-driven progressive upregulation of pro-inflammatory gene expression in stroma. We further demonstrate that transcriptomic pathways elicited in vivo by prototypic microbial molecules are largely recapitulated during aging, thereby supporting the inflammatory basis of age-related adaptations of BM hematopoietic function.

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Complement C1q Activates Canonical Wnt Signaling and Promotes Aging-Related Phenotypes

Cited by 32 publications

References 0 publications

Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver

Complement C1q mediates the expansion of periportal hepatic progenitor cells in senescence-associated inflammatory liver

Tumour‐cell‐derived complement components C1r and C1s promote growth of cutaneous squamous cell carcinoma

Global Transcriptomic Profiling of the Bone Marrow Stromal Microenvironment During Postnatal Development, Aging and Inflammation

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