Nature Cardiovascular Research：巨噬細(xì)胞在缺血性肌損傷血管恢復(fù)中的支持作用

中文摘要：

損傷后的無菌炎癥對于組織恢復(fù)很重要。在受傷的人和小鼠組織中，最近發(fā)現(xiàn)巨噬細(xì)胞在血管周圍積累。本研究調(diào)查巨噬細(xì)胞是否采用對缺血性損傷后恢復(fù)很重要的壁細(xì)胞表型。來自缺血性小鼠肌肉的命運(yùn)定位巨噬細(xì)胞的單細(xì)胞 RNA 測序顯示，具有下調(diào)髓系細(xì)胞基因和上調(diào)壁細(xì)胞基因（包括 PDGFRβ）的巨噬細(xì)胞亞群存在巨噬細(xì)胞向壁細(xì)胞的轉(zhuǎn)換。當(dāng)在分析中包括未拼接的轉(zhuǎn)錄本時(shí)，這一觀察結(jié)果得到了進(jìn)一步加強(qiáng)。巨噬細(xì)胞轉(zhuǎn)換被證明具有功能相關(guān)性，因?yàn)榫奘杉?xì)胞特異性 PDGFRβ 缺乏癥的誘導(dǎo)阻止了其血管周圍巨噬細(xì)胞表型、受損血管成熟和增加血管滲漏，最終降低了肢體功能。總之，成體缺血組織中的巨噬細(xì)胞被證明經(jīng)歷了細(xì)胞程序，在形態(tài)學(xué)、轉(zhuǎn)錄組和功能上類似于壁細(xì)胞，同時(shí)削弱了它們的巨噬細(xì)胞特性。巨噬細(xì)胞到壁細(xì)胞樣表型轉(zhuǎn)換對于恢復(fù)組織功能至關(guān)重要，值得進(jìn)一步探索作為免疫療法促進(jìn)愈合的潛在靶點(diǎn)。

英文摘要：

Sterile inflammation after injury is important for tissue restoration. In injured human and mouse tissues, macrophages were recently found to accumulate perivascularly. This study investigates if macrophages adopt a mural cell phenotype important for restoration after ischemic injury. Single-cell RNA sequencing of fate-mapped macrophages from ischemic mouse muscles demonstrates a macrophage-toward-mural cell switch of a subpopulation of macrophages with downregulated myeloid cell genes and upregulated mural cell genes, including PDGFRβ. This observation was further strengthened when including unspliced transcripts in the analysis. The macrophage switch was proven functionally relevant, as induction of macrophage-specific PDGFRβ deficiency prevented their perivascular macrophage phenotype, impaired vessel maturation and increased vessel leakiness, which ultimately reduced limb function. In conclusion, macrophages in adult ischemic tissue were demonstrated to undergo a cellular program to morphologically, transcriptomically and functionally resemble mural cells while weakening their macrophage identity. The macrophage-to-mural cell-like phenotypic switch is crucial for restoring tissue function and warrants further exploration as a potential target for immunotherapies to enhance healing.

論文信息：

論文題目：Macrophages upregulate mural cell-like markers and support healing of ischemic injury by adopting functions important for vascular support

期刊名稱：Nature Cardiovascular Research

時(shí)間期卷：3, 685–700 (2024)pages685–700 (2024)

在線時(shí)間：2024年6月6日

清除給藥策略：

為了確定巨噬細(xì)胞是否有助于壁細(xì)胞覆蓋，我們在胰島移植前后給予氯膦酸鹽脂質(zhì)體Clodronateliposomes以清除巨噬細(xì)胞。與移植到接受對照脂質(zhì)體（Control Liposomes）的小鼠的胰島相比，氯膦酸鹽脂質(zhì)體（Clodronate Liposomes）處理導(dǎo)致移植胰島中巨噬細(xì)胞被耗竭92.8±0.1%（圖5e）

參考意義：

我們在用荷蘭liposoma品牌Clodronateliposomes清除巨噬細(xì)胞時(shí)，評價(jià)自己的清除體系，可以參照該文獻(xiàn)的圈門策略。時(shí)刻記住，巨噬細(xì)胞的異質(zhì)性，以及在模型發(fā)生和發(fā)展過程中的動態(tài)變化。參考文獻(xiàn)時(shí)，即使一樣的模型，由于采樣時(shí)間點(diǎn)不同，巨噬細(xì)胞的清除，也有可能不太一致。

材料方法：