Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling
Bone marrow injection stimulates hepatic ductular reactions in the absence of injury via macrophage-mediated TWEAK signaling
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DOI：
10.1073/pnas.1302168110
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发表时间：
2013-04-16
影响因子：
11.1
通讯作者：
Forbes, Stuart J.
中科院分区：
文献类型：
--
作者：
Bird, Thomas G.;Lu, Wei-Yu;Forbes, Stuart J.
组织祖细胞是再生治疗的一个有吸引力的靶标。在各种器官中，骨髓细胞（BMC）疗法已显示出有希望的初步结果，但迄今为止，尚未证明明确的机制可以解释所观察到的器官再生益处。组织损伤和再生总是伴随着巨噬细胞浸润，但它们对祖细胞的影响尚不完全清楚，巨噬细胞在器官损伤过程中的多种作用可能会掩盖直接信号传导途径。因此，我们检查了一个没有受伤的模型；单次静脉注射在健康小鼠体内注射未分级的 BMC。这在健康小鼠中引起了导管反应（DR）。我们证明，普通 BMC 内的巨噬细胞负责 DR 的产生、植入受体肝脏并定位于 DR。移植的巨噬细胞原位产生细胞因子 TWEAK（TNF 样弱凋亡诱导剂）。我们继续证明重组 TWEAK 激活 DR，并且 BMC 介导的 DR 是 TWEAK 依赖性的。 DR 伴随着肝脏生长，在没有肝组织损伤的情况下发生，并且可以从患有 DR 的小鼠的肝脏中分离出肝祖细胞。总体而言，这些结果揭示了迄今为止未描述的将巨噬细胞浸润与肝脏中的 DR 联系起来的机制，并强调了再生医学中巨噬细胞衍生细胞疗法的基本原理。
Tissue progenitor cells are an attractive target for regenerative therapy. In various organs, bone marrow cell (BMC) therapy has shown promising preliminary results, but to date no definite mechanism has been demonstrated to account for the observed benefit in organ regeneration. Tissue injury and regeneration is invariably accompanied by macrophage infiltration, but their influence upon the progenitor cells is incompletely understood, and direct signaling pathways may be obscured by the multiple roles of macrophages during organ injury. We therefore examined a model without injury; a single i.v. injection of unfractionated BMCs in healthy mice. This induced ductular reactions (DRs) in healthy mice. We demonstrate that macrophages within the unfractionated BMCs are responsible for the production of DRs, engrafting in the recipient liver and localizing to the DRs. Engrafted macrophages produce the cytokine TWEAK (TNF-like weak inducer of apoptosis) in situ. We go on to show that recombinant TWEAK activates DRs and that BMC mediated DRs are TWEAK dependent. DRs are accompanied by liver growth, occur in the absence of liver tissue injury and hepatic progenitor cells can be isolated from the livers of mice with DRs. Overall these results reveal a hitherto undescribed mechanism linking macrophage infiltration to DRs in the liver and highlight a rationale for macrophage derived cell therapy in regenerative medicine.