McBride Jeffrey D, Liu Xiaochen, Berry William L, Janknecht Ralf, Cheng Rui, Zhou Kelu, Badiavas Evangelos V, Ma Jian-Xing
Department of Cell Biology, University of Oklahoma Health Sciences Center, BSEB 328B, 941 Stanton L. Young Blvd, Oklahoma City, OK, 73104-5020, USA.
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Int J Hematol. 2017 Jun;105(6):748-757. doi: 10.1007/s12185-017-2205-5. Epub 2017 Mar 15.
Members of the family of serine proteinase inhibitors, such as kallistatin, have been shown to inhibit canonical Wnt-TCF/LEF-β-catenin signaling via their interactions with the Wnt co-receptor LRP6. Yet the effects of transgenic overexpression of anti-Wnt serpins on hematopoiesis and lymphopoiesis are not well known. We studied the effects of human kallistatin (SERPINA4) on Wnt reporter activity in various cell types throughout the hematopoietic system and associated impacts on circulating white blood cell profiles. Transgenic overexpression of kallistatin suppressed Wnt-TCF/LEF-β-catenin signaling in bone marrow, as demonstrated using a Wnt reporter mouse. Further, kallistatin overexpression and treatment were associated with reduced Wnt-TCF/LEF-β-catenin activity in CD34 c-kit bone marrow cells and CD19 B lymphocytes, with reduced levels of these populations in bone marrow and peripheral circulation, respectively. The presence of CD3CD4, CD3CD8, and CD3 NK1.1 T lymphocytes were not significantly affected. Our data suggest that overexpression of kallistatin interferes with lymphopoiesis, ultimately impacting the level of circulating CD19 B lymphocytes.
丝氨酸蛋白酶抑制剂家族的成员，如激肽释放酶抑制蛋白，已被证明可通过与Wnt共受体LRP6相互作用来抑制经典的Wnt-TCF/LEF-β-连环蛋白信号传导。然而，抗Wnt丝氨酸蛋白酶抑制剂转基因过表达对造血和淋巴细胞生成的影响尚不清楚。我们研究了人激肽释放酶抑制蛋白（SERPINA4）对整个造血系统中各种细胞类型的Wnt报告基因活性的影响以及对循环白细胞谱的相关影响。使用Wnt报告基因小鼠证明，激肽释放酶抑制蛋白的转基因过表达抑制了骨髓中的Wnt-TCF/LEF-β-连环蛋白信号传导。此外，激肽释放酶抑制蛋白的过表达和处理与CD34 c-kit骨髓细胞和CD19 B淋巴细胞中Wnt-TCF/LEF-β-连环蛋白活性降低有关，分别导致骨髓和外周循环中这些细胞群的水平降低。CD3CD4、CD3CD8和CD3 NK1.1 T淋巴细胞的存在没有受到显著影响。我们的数据表明，激肽释放酶抑制蛋白的过表达会干扰淋巴细胞生成，最终影响循环CD19 B淋巴细胞的水平。
