R-Spondin1 enhances wnt signaling and decreases weight loss in short bowel syndrome zebrafish

Author(s)

Maselli, Kathryn M. ^[1] ; Levin, Gabriel ^{[2, 3]} ; Gee, Kristin M. ^[1] ; Leeflang, Elisabeth J. ^[1] ; Carreira, Ana Claudia O. ^{[2, 3, 4]} ; Sogayar, Mari Cleide ^{[2, 3, 5]} ; Grikscheit, Tracy C. ^{[1, 6]}

Affiliation

^[1] Childrens Hosp Los Angeles, Div Pediat Surg, Los Angeles, CA 90027 - USA

^[2] Univ Sao Paulo, Cell & Mol Therapy Ctr NUCEL, Sch Med, Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Inst Biomed Sci, Interunits Grad Program Biotechnol, Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo FMVZ USP, Sch Vet Med & Anim Sci, Dept Surg, Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Chem Inst, Biochem Dept, Sao Paulo, SP - Brazil

^[6] Univ Southern Calif, Keck Sch Med, Dept Surg, Los Angeles, CA 90033 - USA

• Document type: Journal article
• Source: BIOCHEMISTRY AND BIOPHYSICS REPORTS; v. 25, MAR 2021.
• Web of Science Citations: 0

Abstract

Background: R-spondins, including R-spondin 1 (RSPO1), are a family of Wnt ligands that help to activate the canonical Wnt/beta-catenin pathway, which is critical for intestinal epithelial cell proliferation and maintenance of intestinal stem cells. This proliferation underpins the epithelial expansion, or intestinal adaptation (IA), that occurs following massive bowel resection and short bowel syndrome (SBS). The purpose of this study was to identify if recombinant human RSPO1 (rhRSPO1) could be serially administered to SBS zebrafish to enhance cellular proliferation and IA. Methods: Adult male zebrafish were assigned to four groups: sham + PBS, SBS + PBS, sham + rhRSPO1, and SBS + rhRSPO1. Sham fish had a laparotomy alone. SBS fish had a laparotomy with distal intestinal ligation and creation of a proximal stoma. Fish were weighed at initial surgery and then weekly. rhRSPO1 was administered post-operatively following either a one- or two-week dosing schedule with either 3 or 5 intraperitoneal injections, respectively. Fish were harvested at 7 or 14 days with intestinal segments collected for analysis. Results: Repeated intraperitoneal injection of rhRSPO1 was feasible and well tolerated. At 7 days, intestinal epithelial proliferation was increased by rhRSPO1. At 14 days, SBS + rhRSPO1 fish lost significantly less weight than SBS + PBS fish. Measurements of intestinal surface area were not increased by rhRSPO1 administration but immunofluorescent staining for beta-catenin and gene expression for cyclin D1 was increased. Conclusions: Intraperitoneal injection of rhRSPO1 decreased weight loss in SBS zebrafish with increased beta-catenin + cells and cyclin D1 expression at 14 days, indicating improved weight maintenance might result from increased activation of the canonical Wnt pathway. (AU)

• FAPESP's process: 16/05311-2 - Regenerative medicine aiming at therapy for chronic degenerative diseases (cancer and diabetes)
• Grantee: Mari Cleide Sogayar
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/11128-3 - Analysis of the therapeutic potential of the human recombinant RSPO1 protein in regeneration of small intestine in an animal model using tissue Engeneering technologies
• Grantee: Gabriel Levin
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/01072-6 - Analysis of the therapeutic potential of the human recombinant RSPO1 protein in regeneration of the small intestine in an animal model using tissue engineering technologies
• Grantee: Gabriel Levin
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)