ORIGINAL ARTICLE Heat Shock Protein A4 Controls Cell Migration and Gastric Ulcer Healing Toshiharu Sakurai • Hiroshi Kashida • Satoru Hagiwara • Naoshi Nishida • Tomohiro Watanabe • Jun Fujita • Masatoshi Kudo Received: 26 November 2014 / Accepted: 22 January 2015 / Published online: 6 February 2015 Ó Springer Science+Business Media New York 2015 Abstract Aims and Methods Heat shock protein A4 (HSPA4, also called Apg-2), a member of the HSP110 family, regulates the immune response in the gut. Here, we assessed the involvement of HSPA4 in gastric ulcer healing by using fibroblasts from wild-type and HSPA4-deficient mice, a murine gastric ulcer model, and samples from 65 patients with gastric cancer. Results HSPA4 expression was inversely correlated with gastric ulcer healing following endoscopic resection of gas- tric cancer. In the human gastric mucosa, the expression of HSPA4 was inversely correlated with the expression of stromal cell-derived factor 1 (SDF-1), its cognate receptor CXC chemokine receptor 4 (CXCR4), the stromal cell marker vimentin, and the epithelial–mesenchymal transition regula- tor Twist. HSPA4 was overexpressed in stromal cells as well as in human gastric cancer cells. HSPA4 deficiency increased the expression of SDF-1 and CXCR4, as well as the number of fibroblast-specific protein 1-positive cells, leading to accel- erated ulcer healing in the murine gastric ulcer model. Deletion of HSPA4 promoted cell migration in mouse fi- broblasts through increased expression of SDF-1 and Twist. Conclusion HSPA4 regulates the expression of SDF-1 and Twist in fibroblasts, thereby controlling gastric ulcer healing. Keywords HSP Á SDF-1 Á CXCR4 Á Twist Á FSP-1 Á Gastric cancer Abbreviations CTGF Connective tissue growth factor CXCR4 CXC chemokine receptor 4 DAPI 4,6 0 -Diamidino-2-phenylindole EMT Epithelial–mesenchymal transition ESD Endoscopic submucosal dissection EMR Endoscopic mucosal resection FSP-1 Fibroblast-specific protein 1 HSP Heat shock protein IBD Inflammatory bowel disease MEF Mouse embryonic fibroblast SDF-1 Stromal cell-derived factor 1 WT Wild type Introduction Wound healing comprises a complex and coordinated series of events involving inflammation, tissue deposition, remodeling, and scarring. Fibroblasts are known to be essential in tissue repair [1]. They move to the affected area upon wound formation and synthesize collagen together with other extracellular matrix components, thereby gen- erating the conditions required to repair the wound. The Electronic supplementary material The online version of this article (doi:10.1007/s10620-015-3561-8) contains supplementary material, which is available to authorized users. T. Sakurai (&) Á H. Kashida Á S. Hagiwara Á N. Nishida Á M. Kudo Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan e-mail: sakurai@med.kindai.ac.jp T. Watanabe Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan J. Fujita Department of Clinical Molecular Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan 123 Dig Dis Sci (2015) 60:850–857 DOI 10.1007/s10620-015-3561-8