Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by vasculopathy and tissue fibrosis. Although the most recognizable manifestation is skin disease, SSc can affect the lungs, heart, gastrointestinal tract and kidney resulting in significant morbidity and mortality. Digital ulcers and gangrene caused by progressive vasculopathy are also critical complications of SSc, strongly affecting physical function. Although animal models mimicking its entire pathology were previously unavailable, we have recently established mice with double heterozygous deficiency of the Klf5 and Fli1 genes, both of which are epigenetically suppressed in SSc dermal fibroblasts, spontaneously developing features of SSc, including fibrosis and vasculopathy of the skin and lung, B cell activation, and autoantibody production. In this study, we further investigated if Klf5+/-;Fli1+/- mice recapitulate delayed wound healing and cardiac and intestinal involvement characteristic of SSc.
Methods: Four full-thickness excisional wounds per mouse were generated by an 8-mm biopsy punch on the back skin. The process of wound healing was assessed macroscopically and histologically. Angiogenesis and vasculogenesis were assayed by ex vivo retinal explant culture assay and in vivo matrigel plug assay, respectively. Myocardium, small intestine, and colon samples were analyzed by quantitative reverse transcription PCR, immunoblotting, and immunohistochemistry.
Results: Wound healing was markedly delayed in Klf5+/-;Fli1+/- mice compared with wild type (WT) mice. In scar tissue, vascular network was poorly developed in Klf5+/-;Fli1+/- mice compared with WT mice. However, at day 5 after wounding the number and the diameter of newly formed vessels in granulation tissue were significantly increased in Klf5+/-;Fli1+/- mice compared with WT mice. In ex vivo retinal explants culture assay, angiogenesis was markedly accelerated in Klf5+/-;Fli1+/- mice. In contrast, vasculogenesis was impaired in Klf5+/-;Fli1+/- mice when evaluated by in vivo matrigel plug assay. Importantly, the stimulation of angiogenesis- and vasculogenesis-related factors suppressed the expression of both KLF5 and Fli1 in human dermal microvascular endothelial cells and murine mesenchymal stem cells, respectively. With respect to visceral organ involvement, apoptotic vascular endothelial cells were evident together with interstitial fibrosis in heart and dysfunction of intestine due to a switch from a contractile to synthetic phenotype of intestinal smooth muscle cells was suspected.
Conclusion: Klf5+/-;Fli1+/- mice mimic delayed wound healing and cardiac and intestinal involvement of SSc. Delayed wound healing seems to be associated with accelerated angiogenesis and suppressed vasculogenesis together with impaired anastomosis of newly formed vessels with pre-existing ones. Cardiac fibrosis and intestinal dysfunction were due to endothelial apoptosis and a phenotypical alteration of intestinal smooth muscle cells, respectively. These results indicate that Klf5+/-;Fli1+/- mice could serve as a reliable tool to investigate the details of disease process underlying SSc.
To cite this abstract in AMA style:Nakamura K, Asano Y, Miyagawa T, Hirabayashi M, Yamashita T, Saigusa R, Miura S, Toyama T, Takahashi T, Ichimura Y, Taniguchi T, Yoshizaki A, Trojanowska M, Sato S. Klf5+/-;Fli1+/- Mice Recapitulate Protracted Wound Healing and Cardiac and Intestinal Involvement Associated with Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/klf5-fli1-mice-recapitulate-protracted-wound-healing-and-cardiac-and-intestinal-involvement-associated-with-systemic-sclerosis/. Accessed August 3, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/klf5-fli1-mice-recapitulate-protracted-wound-healing-and-cardiac-and-intestinal-involvement-associated-with-systemic-sclerosis/