Vascular calcifying progenitor cells possess bidirectional differentiation potentials.
Vascular calcifying progenitor cells possess bidirectional differentiation potentials.
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DOI：
10.1371/journal.pbio.1001534
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发表时间：
2013
期刊：
影响因子：
9.8
通讯作者：
Kim HS
中科院分区：
文献类型：
--
作者：
Cho HJ;Cho HJ;Lee HJ;Song MK;Seo JY;Bae YH;Kim JY;Lee HY;Lee W;Koo BK;Oh BH;Park YB;Kim HS
血管中的钙化祖细胞有可能分化为促进钙积聚或逆转钙积聚的细胞，PPAR治疗？可以改变这个分化的方向。血管钙化是动脉粥样硬化的晚期特征，目前尚无有效的治疗方法。为了研究钙化的调节或逆转，我们鉴定了钙化祖细胞并研究了它们的钙化/脱钙电位。使用Sca-1和PDGFRα标记物将小鼠主动脉细胞分为四组。Sca-1+ （Sca-1+/PDGFRα+和Sca-1+/PDGFRα−）祖细胞比Sca-1−（Sca-1−/PDGFRα+和Sca-1−/PDGFRα−）祖细胞表现出更大的成骨分化潜能。在Sca-1+祖细胞群体中，Sca-1+/PDGFRα -细胞具有向成骨细胞和破骨细胞谱系双向分化的潜力，而Sca-1+/PDGFRα+细胞向成骨细胞谱系单向分化。当使用过氧化物酶体增殖物激活受体γ (PPARγ)激动剂处理时，Sca-1+/PDGFRα -细胞优先分化为破骨细胞样细胞。动脉内的Sca-1+祖细胞来源于骨髓（BM），可以克隆扩增。血管驻留bm来源的Sca-1+钙化祖细胞显示出非造血、间充质特征。为了评估体内钙化的调节，我们建立了异位和动脉粥样硬化钙化模型。计算机断层扫描显示，ca-1+祖细胞增加异位钙化的体积和钙评分。然而，与未处理的细胞相比，经PPARγ激动剂处理的Sca-1+/PDGFRα−细胞的骨形成减少了2倍。向Apoe - / -小鼠全身输注Sca-1+/PDGFRα -细胞可增加钙化动脉粥样硬化斑块的严重程度。然而，激活PPARγ的Sca-1+/PDGFRα−细胞显示斑块严重程度明显降低。免疫荧光染色显示，ca-1+/PDGFRα−细胞主要表达骨钙素；然而，PPARγ的激活引发了核因子-κB （RANK）受体激活因子的表达，表明它们在体内的双向命运。这些发现表明，脑卒中衍生的一种亚型和血管驻留祖细胞提供了预防血管钙化的治疗靶点，而激活PPARγ可能是逆转钙化的一种选择。动脉粥样硬化包括动脉硬化，可导致心脏病。血管中的钙积累有助于这一过程，而这一过程是由促进钙积累的细胞（成骨细胞）和逆转钙积累的细胞（破骨细胞）调节的。在这项研究中，我们表明血管中的血管钙化祖细胞具有成为成骨细胞或破骨细胞的潜力，并且药物可以推动这些细胞成为破骨细胞而不是成骨细胞。同时表达Sca-1和PDGFRα细胞表面蛋白的祖细胞更倾向于向成骨细胞分化，而仅表达Sca-1的细胞可以双向向成骨细胞或破骨细胞分化。此外，用PPARγ激动剂治疗可以改变Sca-1+/PDGFRα -祖细胞向破骨细胞样细胞的分化方向，而不能影响Sca-1+/PDGFRα+祖细胞的命运。这些结果为逆转血管钙积聚提供了新的治疗靶点。
Calcifying progenitor cells in blood vessels have the potential to differentiate into cells that either promote calcium accumulation or reverse accumulation, and treatment with PPAR? can shift the direction of this differentiation. Vascular calcification is an advanced feature of atherosclerosis for which no effective therapy is available. To investigate the modulation or reversal of calcification, we identified calcifying progenitor cells and investigated their calcifying/decalcifying potentials. Cells from the aortas of mice were sorted into four groups using Sca-1 and PDGFRα markers. Sca-1+ (Sca-1+/PDGFRα+ and Sca-1+/PDGFRα−) progenitor cells exhibited greater osteoblastic differentiation potentials than Sca-1− (Sca-1−/PDGFRα+ and Sca-1−/PDGFRα−) progenitor cells. Among Sca-1+ progenitor populations, Sca-1+/PDGFRα− cells possessed bidirectional differentiation potentials towards both osteoblastic and osteoclastic lineages, whereas Sca-1+/PDGFRα+ cells differentiated into an osteoblastic lineage unidirectionally. When treated with a peroxisome proliferator activated receptor γ (PPARγ) agonist, Sca-1+/PDGFRα− cells preferentially differentiated into osteoclast-like cells. Sca-1+ progenitor cells in the artery originated from the bone marrow (BM) and could be clonally expanded. Vessel-resident BM-derived Sca-1+ calcifying progenitor cells displayed nonhematopoietic, mesenchymal characteristics. To evaluate the modulation of in vivo calcification, we established models of ectopic and atherosclerotic calcification. Computed tomography indicated that Sca-1+ progenitor cells increased the volume and calcium scores of ectopic calcification. However, Sca-1+/PDGFRα− cells treated with a PPARγ agonist decreased bone formation 2-fold compared with untreated cells. Systemic infusion of Sca-1+/PDGFRα− cells into Apoe−/− mice increased the severity of calcified atherosclerotic plaques. However, Sca-1+/PDGFRα− cells in which PPARγ was activated displayed markedly decreased plaque severity. Immunofluorescent staining indicated that Sca-1+/PDGFRα− cells mainly expressed osteocalcin; however, activation of PPARγ triggered receptor activator for nuclear factor-κB (RANK) expression, indicating their bidirectional fate in vivo. These findings suggest that a subtype of BM-derived and vessel-resident progenitor cells offer a therapeutic target for the prevention of vascular calcification and that PPARγ activation may be an option to reverse calcification. Atherosclerosis involves hardening of the arteries and can lead to heart disease. Calcium accumulation in blood vessels contributes to this process, and this process is regulated by cells that promote calcium accumulation (osteoblasts) and cells that reverse the accumulation (osteoclasts). In this study, we show that vascular calcifying progenitor cells in the blood vessel have the potential to become either osteoblasts or osteoclasts, and that a drug can push these cells towards becoming osteoclasts instead of osteoblasts. Progenitor cells that express both Sca-1 and PDGFRα cell surface proteins were more committed to differentiate into osteoblasts, while cells that only expressed Sca-1 could differentiate into osteoblasts or osteoclasts in a bidirectional manner. Moreover, treatment with a PPARγ agonist could shift the direction of differentiation of Sca-1+/PDGFRα− progenitor cells toward osteoclast-like cells, whereas it cannot influence the fates of Sca-1+/PDGFRα+ progenitors. These results offer new therapeutic targets for reversing calcium accumulation in blood vessels.
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