Critical Roles of Muscle-Secreted Angiogenic Factors in Therapeutic Neovascularization
Critical Roles of Muscle-Secreted Angiogenic Factors in Therapeutic Neovascularization
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DOI：
10.1161/01.res.0000219901.13974.15
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发表时间：
2006-05
影响因子：
20.1
通讯作者：
Kaoru Tateno;T. Minamino;H. Toko;H. Akazawa;N. Shimizu;S. Takeda;T. Kunieda;Hideyuki Miyauchi
中科院分区：
文献类型：
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作者：
Kaoru Tateno;T. Minamino;H. Toko;H. Akazawa;N. Shimizu;S. Takeda;T. Kunieda;Hideyuki Miyauchi
外周血中骨髓来源的内皮祖细胞的发现促进了对各种人类疾病的细胞治疗潜力的深入研究。越来越多的证据表明，骨髓单个核细胞植入有效地促进缺血组织中的新血管形成。也有报道称，植入的细胞不仅被整合到新形成的血管中，而且还分泌血管生成因子。然而，细胞疗法改善组织缺血的机制仍然不清楚。我们招募了29名“无选择”的严重肢体缺血患者，并通过外周血单个核细胞植入治疗缺血肢体。使用外周单核细胞的细胞疗法对于治疗肢体缺血是非常有效的，并且其功效与血管生成因子，特别是白细胞介素-1（IL-1）的血浆水平的增加相关。然后，我们研究了肢体缺血的实验模型，使用IL-1缺陷小鼠。植入IL-1缺陷的单核细胞改善组织缺血有效的野生型细胞。野生型和IL-1缺乏的单核细胞增加IL-1的表达，从而诱导血管生成因子在缺血肢体的肌肉细胞在相似的程度。相反，肌细胞不能分泌IL-1显著降低了血管生成因子的诱导，并损害了细胞植入的新血管形成。植入的细胞不分泌足够用于新血管形成的血管生成因子，而是刺激肌肉细胞产生血管生成因子，从而促进缺血组织中的新血管形成。进一步的研究将使我们能够开发出更有效的治疗缺血性血管疾病的方法。
The discovery of bone marrow–derived endothelial progenitors in the peripheral blood has promoted intensive studies on the potential of cell therapy for various human diseases. Accumulating evidence has suggested that implantation of bone marrow mononuclear cells effectively promotes neovascularization in ischemic tissues. It has also been reported that the implanted cells are incorporated not only into the newly formed vessels but also secrete angiogenic factors. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. We enrolled 29 “no-option” patients with critical limb ischemia and treated ischemic limbs by implantation of peripheral mononuclear cells. Cell therapy using peripheral mononuclear cells was very effective for the treatment of limb ischemia, and its efficacy was associated with increases in the plasma levels of angiogenic factors, in particular interleukin-1 (IL-1). We then examined an experimental model of limb ischemia using IL-1–deficient mice. Implantation of IL-1–deficient mononuclear cells improved tissue ischemia as efficiently as that of wild-type cells. Both wild-type and IL-1–deficient mononuclear cells increased expression of IL-1 and thus induced angiogenic factors in muscle cells of ischemic limbs to a similar extent. In contrast, inability of muscle cells to secrete IL-1 markedly reduces induction of angiogenic factors and impairs neovascularization by cell implantation. Implanted cells do not secret angiogenic factors sufficient for neovascularization but, instead, stimulate muscle cells to produce angiogenic factors, thereby promoting neovascularization in ischemic tissues. Further studies will allow us to develop more effective treatments for ischemic vascular disease.