Regulation of adipogenic differentiation by LAR tyrosine phosphatase in human mesenchymal stem cells and 3T3-L1 preadipocytes
Regulation of adipogenic differentiation by LAR tyrosine phosphatase in human mesenchymal stem cells and 3T3-L1 preadipocytes
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DOI：
10.1242/jcs.053009
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发表时间：
2009-11-15
影响因子：
4
通讯作者：
Lee, Sang-Chul
中科院分区：
文献类型：
--
作者：
Kim, Won-Kon;Jung, Hyeyun;Lee, Sang-Chul
间充质干细胞（MSC）是多能成体干细胞，可以分化成多种中胚层谱系细胞。间充质干细胞在组织工程和治疗应用中具有巨大潜力；然而，这些细胞在实验室中的低分化和增殖效率是其治疗用途的根本障碍，这主要是由于缺乏有关分化成不同谱系的详细信号转导机制的信息。借助蛋白质酪氨酸磷酸酶分析研究，我们发现在 MSC 的早期脂肪形成阶段，白细胞共同抗原相关 (LAR) 酪氨酸磷酸酶的表达显着降低。内源性 LAR 的敲低诱导脂肪形成分化的显着增加，而其过度表达则导致 3T3-L1 前脂肪细胞和 MSC 的脂肪形成分化减少。 LAR 降低胰岛素受体的酪氨酸磷酸化，进而导致接头蛋白 IRS-1 及其下游分子 Akt（也称为 PKB）的磷酸化降低。我们认为 LAR 作为脂肪生成的负调节因子。此外，我们的数据支持 LAR 控制成骨细胞和脂肪细胞分化之间平衡的可能性。总的来说，我们的研究结果有助于阐明 LAR 活性在 MSC 分化中的潜在机制，并表明 LAR 是控制干细胞分化的候选靶蛋白。
Mesenchymal stem cells (MSCs) are multipotent adult stem cells that can differentiate into a variety of mesodermal-lineage cells. MSCs have significant potential in tissue engineering and therapeutic applications; however, the low differentiation and proliferation efficiencies of these cells in the laboratory are fundamental obstacles to their therapeutic use, mainly owing to the lack of information on the detailed signal-transduction mechanisms of differentiation into distinct lineages. With the aid of protein-tyrosine-phosphatase profiling studies, we show that the expression of leukocyte common antigen related (LAR) tyrosine phosphatase is significantly decreased during the early adipogenic stages of MSCs. Knockdown of endogenous LAR induced a dramatic increase in adipogenic differentiation, whereas its overexpression led to decreased adipogenic differentiation in both 3T3-L1 preadipocytes and MSCs. LAR reduces tyrosine phosphorylation of the insulin receptor, in turn leading to decreased phosphorylation of the adaptor protein IRS-1 and its downstream molecule Akt (also known as PKB). We propose that LAR functions as a negative regulator of adipogenesis. Furthermore, our data support the possibility that LAR controls the balance between osteoblast and adipocyte differentiation. Overall, our findings contribute to the clarification of the mechanisms underlying LAR activity in the differentiation of MSCs and suggest that LAR is a candidate target protein for the control of stem-cell differentiation.