巨噬細胞與心臟再生作用

心力衰竭幾乎是所有心血管疾病的結果。心臟移植是目前對末期心力衰竭的唯一療法，但屍心長期供不應求，移植後仍因排異反應而逐漸喪失其功能，顯然需要更好療法。巨噬細胞（macrophage, Mφ）是心臟固有細胞之一，具有極高可塑性，可隨著微環境的刺激而轉化為促發炎的M1和促組織修復的M2表型來參與整個心臟癒合過程；研究發現，斑馬魚和新生小鼠在消耗Mφ後便失去心臟再生能力，顯示Mφ是極具潛力的治療目標。本研究綜述了心臟損傷後的癒合過程，重點介紹Mφ的表型轉化和功能，並通過比較再生與非再生動物心臟癒合過程的差別，嘗試找出具潛力的治療方向和待解決的困難。結果發現新生小鼠在心臟癒合時僅擴增心臟駐留的類M2-Mφ，並招募較少中性粒細胞（neutrophils, NE），而成年小鼠則主要招募M1-Mφ，NE的招募也相對較多；雖然人為減少M1-Mφ的招募的確有助於心臟癒合，但過度減少卻可能造成心臟修復不良和纖維化。因此，相比過去減少M1-Mφ的療法來說，改為增加能促進NE清除、細胞外基質重組和血管生成的M2-Mφ可能更具治療潛力，但根據目前的理論架構，要在不影響M1-Mφ的情況下增加M2-Mφ群體數量是困難的，所以，更深入透徹地瞭解Mφ的招募轉化機制，將會是心臟再生治療方面首要突破的瓶頸。

Heart failure is the outcome of almost all cardiovascular diseases. Cardiac transplantation remains the only true “cure” for end-stage disease. However, challenges causing by insufficient donor heart and gradually function losses due to transplant rejection highlight the demand of de-novo therapies. Macrophages (Mφ) are one of the constituent cells within heart, with extremely high plasticity, which can be transformed into pro-inflammatory M1 and reparative M2 phenotypes, depend on the stimulation of the microenvironment, in order to participate in the whole healing process post-myocardial infarction (MI). Researches found that zebrafish and neonatal mice will lose their cardiac regeneration capacity after Mφ depletion, showing that Mφ is a potential therapeutic target. This study reviews the healing process post-cardiac injury, focus on the phenotyping and function of Mφ, and attempts to identify potential therapy and outstanding issues through comparing the cardiac healing processes between regenerative and non-regenerative animal models. In conclusion, it was found that, during healing process post-MI, neonatal mice only expand the cardiac resident M2-like-Mφ with fewer recruitment of neutrophils (NE) in heart, while adult mice mainly recruits M1-Mφ and more NE. Although reducing M1-Mφ recruitment is beneficial, excessive may compromises cardiac healing and increased fibrosis. Thus, increasing M2-Mφ, which can promote NE clearance, extracellular matrix remodeling, and angiogenesis may be more therapeutically potential rather than reducing M1-Mφ. However, according to current theories, expanding the M2-Mφ population without affecting M1-Mφ may be difficult. Therefore, deeper understanding of the recruitment and phenotyping mechanism of Mφ has become one of the major goal of cardiac regeneration therapy.