Mindin (SPON2) Is Essential for Cutaneous Fibrogenesis in a Mouse Model of Systemic Sclerosis

Rana, Isha; Kataria, Sunny; Tan, Tuan Lin; Hajam, Edries Yousaf; Kashyap, Deepak; Saha, Dyuti; Ajnabi, Johan; Paul, Sayan; Jayappa, Shashank; Kumar, Pankaj; Zaarour, Rania F.; Haarshaadri, J; Kansagara, Gaurav; Rizvi, Abrar; Zirmire, Ravindra K.; Badarinath, Krithika; Khedkar, Sneha Uday; Chandra, Yogesh; Samuel, Rekha; George, Renu; Danda, Debashish; Jacob, Paul; Dey, Rakesh; Dhandapany, Perundurai S.; He, You–Wen; Varga, John; Varghese, Shyni

doi:10.1016/j.jid.2022.10.011

Cited by 5 publications

(14 citation statements)

References 75 publications

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“…To interrogate whether the Snail tg skin also exhibits early vasculopathy that precedes the thickening of the dermis, we performed a developmental analysis of the vasculopathy phenotype. Previously, we have observed increased dermal thickening (a readout for fibrosis) as early as postnatal day 9 in the Snail tg skin which increases progressively to adulthood 23 . We therefore analysed the vascular defects via PECAM-1 staining at postnatal (P) days 3, 7, and 9 and observed an increased vessel density as early as P3 in the Snail tg skin (Figure 2A).…”

Section: Resultsmentioning

confidence: 84%

“…Using a mouse model that recapitulates many of the clinical features of SSc 23 , we have elucidated the mechanisms underlying vasculopathy that is a hallmark of this and many fibrotic diseases. Our work positions Angptl2 secreted from Snail tg keratinocytes as a major driver of the vasculopathy observed in the fibrotic skin.…”

Section: Discussionmentioning

confidence: 99%

“…The Snail tg mouse skin recapitulates various histological and molecular features of SSc such as the increased dermal thickness, ECM deposition and increased inflammation. Similar to the progression of SSc, the fibrosis in the Snail tg mouse is long-lasting and originates in the skin and progresses to the involvement of internal organs 23 . Although defects related to the blood vessels such as Raynaud’s phenomenon was observed in the Snail tg skin 23 , it remains to be determined to what extent the Snail tg skin recapitulates SSc vasculopathy.…”

Section: Introductionmentioning

confidence: 99%

“…Similar to the progression of SSc, the fibrosis in the Snail tg mouse is long-lasting and originates in the skin and progresses to the involvement of internal organs 23 . Although defects related to the blood vessels such as Raynaud’s phenomenon was observed in the Snail tg skin 23 , it remains to be determined to what extent the Snail tg skin recapitulates SSc vasculopathy. The presence of SSc-like vascular defects in the Snail tg skin would position this mouse model as a platform to elucidate the underlying mechanisms of SSc vasculopathy and the contribution of vascular defects to fibrogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Saha,

Thannimangalath,

Pincha

et al. 2023

Preprint

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Vasculopathy is a common hallmark of various fibrotic disorders including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill-defined. In SSc the vasculopathy typically precedes the onset of fibrosis and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that Angiopoietin-like protein 2 (Angptl2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, Angptl2 upregulates pro-fibrotic genes, downregulates the tight junction protein Claudin 5, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and consequently vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, Angptl2 emerges as a promising early biomarker of the disease and inhibiting the vasculopathy inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to the treatment of fibrotic diseases by targeting the vascular defects.

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Section: Resultsmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Saha,

Thannimangalath,

Pincha

et al. 2023

Preprint

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“…Loss of function in Mindin was further shown to rescue the effect of Snail overexpression on epidermal expansion and in squamous cell carcinoma xenograft models [ 165 ]. In addition, a higher SNAI1 expression was found in the epidermis of patients with systemic sclerosis, linking its function in skin fibrosis to the induction of inflammation and fibroblast-mediated collagen secretion [ 167 , 168 ]. Mindin and fibulin 5 inhibition can rescue Snail-induced skin fibrosis, making them potential therapeutic targets.…”

Section: Matricellular Proteins In Stem Cell Regulation During Homeos...mentioning

confidence: 99%

Matricellular Proteins in the Homeostasis, Regeneration, and Aging of Skin

Raja,

Clarin,

Yanagisawa

2023

IJMS

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Matricellular proteins are secreted extracellular proteins that bear no primary structural functions but play crucial roles in tissue remodeling during development, homeostasis, and aging. Despite their low expression after birth, matricellular proteins within skin compartments support the structural function of many extracellular matrix proteins, such as collagens. In this review, we summarize the function of matricellular proteins in skin stem cell niches that influence stem cells’ fate and self-renewal ability. In the epidermal stem cell niche, fibulin 7 promotes epidermal stem cells’ heterogeneity and fitness into old age, and the transforming growth factor-β—induced protein ig-h3 (TGFBI)—enhances epidermal stem cell growth and wound healing. In the hair follicle stem cell niche, matricellular proteins such as periostin, tenascin C, SPARC, fibulin 1, CCN2, and R-Spondin 2 and 3 modulate stem cell activity during the hair cycle and may stabilize arrector pili muscle attachment to the hair follicle during piloerections (goosebumps). In skin wound healing, matricellular proteins are upregulated, and their functions have been examined in various gain-and-loss-of-function studies. However, much remains unknown concerning whether these proteins modulate skin stem cell behavior, plasticity, or cell–cell communications during wound healing and aging, leaving a new avenue for future studies.

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Ablation of collagen XII disturbs joint extracellular matrix organization and causes patellar subluxation

Zhu¹,

Metzen²,

Hopkinson³

et al. 2023

iScience

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Mindin (SPON2) Is Essential for Cutaneous Fibrogenesis in a Mouse Model of Systemic Sclerosis

Cited by 5 publications

References 75 publications

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

Matricellular Proteins in the Homeostasis, Regeneration, and Aging of Skin

Ablation of collagen XII disturbs joint extracellular matrix organization and causes patellar subluxation

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