Molecular Pathogenesis of Genetic and Inherited Diseases Critical Roles of Lysosomal Acid Lipase in Myelopoiesis
Molecular Pathogenesis of Genetic and Inherited Diseases Critical Roles of Lysosomal Acid Lipase in Myelopoiesis
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发表时间：
2010
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通讯作者：
P. Qu;W. C. Shelley;M. Yoder;Lingyan Wu;H. Du;Cong Yan
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作者：
P. Qu;W. C. Shelley;M. Yoder;Lingyan Wu;H. Du;Cong Yan
Lysosomal acid lipase (LAL) is a key enzyme that cleaves cholesteryl esters and triglycerides to generate free fatty acids and cholesterol in lysosomes. Genetic ablation of the lal gene (lal / ) in mice has resulted in a systemic increase of macrophages and neutrophils, causing severe inflammation and pathogenesis in multiple organs. We hypothesized that aberrant growth and differentiation of myeloid cells in lal / mice arises from dysregulated production of progenitor cells in the bone marrow. Indeed, lal / mice displayed increased numbers of primitive lin Sca-1 c-Kit (LSK) cells and granulocyte-macrophage precursors (GMP). Increased high proliferative potential colony-forming cells (HPP-CFC) were enumerated from cultured lal / bone marrow cells, as were significantly more CFU-GM, CFU-G, and CFU-M colonies. As a consequence, lal / mice developed significant myeloid infiltration, particularly with CD11b /Gr-1 myeloid-derived suppressive cells in multiple organs. Both decreased apoptosis and increased proliferation contribute to the systemic increase of myeloid cells in lal / myeloid cells. These lal / CD11b /Gr-1 cells displayed suppressive activity on T cell proliferation and function in vitro. Bone marrow chimeras confirmed that the myeloproliferative disorder in lal / mice was primarily attributable to autonomous defects in myeloid progenitor cells , although the hematopoietic microenvironment in the lal / mice did not support hematopoiesis normally. These results provide evidence that LAL is an important regulator of myelopoiesis during hematopoietic development , differentiation, and homeostasis. (Am J Pathol 2010, 176:2394–2404; DOI: 10.2353/ajpath.2010.091063)
