Nature Cardiovascular Research：巨噬細胞在缺血性肌損傷血管恢復中的支持作用

中文摘要：

損傷后的無(wú)菌炎癥對于組織恢復很重要。在受傷的人和小鼠組織中，最近發(fā)現巨噬細胞在血管周?chē)e累。本研究調查巨噬細胞是否采用對缺血性損傷后恢復很重要的壁細胞表型。來(lái)自缺血性小鼠肌肉的命運定位巨噬細胞的單細胞 RNA 測序顯示，具有下調髓系細胞基因和上調壁細胞基因（包括 PDGFRβ）的巨噬細胞亞群存在巨噬細胞向壁細胞的轉換。當在分析中包括未拼接的轉錄本時(shí)，這一觀(guān)察結果得到了進(jìn)一步加強。巨噬細胞轉換被證明具有功能相關(guān)性，因為巨噬細胞特異性 PDGFRβ 缺乏癥的誘導阻止了其血管周?chē)奘杉毎硇?、受損血管成熟和增加血管滲漏，最終降低了肢體功能?？傊?，成體缺血組織中的巨噬細胞被證明經(jīng)歷了細胞程序，在形態(tài)學(xué)、轉錄組和功能上類(lèi)似于壁細胞，同時(shí)削弱了它們的巨噬細胞特性。巨噬細胞到壁細胞樣表型轉換對于恢復組織功能至關(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(chēng)：Nature Cardiovascular Research

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

在線(xiàn)時(shí)間：2024年6月6日

清除給藥策略：

為了確定巨噬細胞是否有助于壁細胞覆蓋，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）處理導致移植胰島中巨噬細胞被耗竭92.8±0.1%（圖5e）

參考意義：

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

材料方法：