Cardiovascular diseases (CVDs東身) are the number o從車ne cause of death global可明ly, responsible for 31% of all h影兒uman mortalities. This is in購畫 part due to lifestyle but also見媽 because the human heart is incapable白化 of functional regenera的頻tion following injury or onset of disea弟如se. In contrast, cardiac rege地美neration can occur in lower ver綠數tebrates and was first id資讀entified in zebrafish where surgica遠坐l resection of the adult heart le電站ads to complete regenerat黃坐ion within 60 days (1). 嗎公Remarkably, it was懂相 later shown that the he照不arts of neonatal mice could also f為報ully regenerate following the removal 謝著of 15% of the left ventricle服很 (2). In both cases, the regenerative r制理esponse is a result of prol有好iferation of pre-existing cardiomyoc短離ytes with complete regressio一影n of fibrosis (scarring) (2,3,道信4).

In a recent paper, Aghajanian數劇 et al (5) have taken adva鐘水ntage of the “Immunor南生evolution” and current breakthr光店oughs in cancer therapy achieved by 大場redirecting cytotoxi長書c T cells to recognize spe件器cific antigens on cancer cells using錢鐘 either a modified T 自劇cell receptor or a chimeric antigen 窗讀receptor (CAR) (6)師風. In the current paper, it 了湖was hypothesized that engineered T ce水黃lls could also be used to targe工月t cardiac fibrobla你白sts and ultimately eliminate excessive 不間fibrosis in the heart. Proof-窗知of-principle was carri器民ed out by the generation of a mouse mod黑刀el in which a xenogeneic mark鄉子er (ovalbumin peptide, OVA) was 森輛expressed on cardiac fibrobl拿山asts following c什說ardiac injury induce體和d by fusion of angiotensin II a分地nd phenylephrine (AngII和兵/PE). In these m玩知ice, significant fibrosis was observed外愛 in the myocardium, consistent wit動船h previous reports (7)明動. When retrovirus transduced CD8+ T司銀 cells expressing a cognate T ce場少ll receptor against OVA were來兵 administered to the mice, si城樂gnificantly less cardia事就c fibrosis and cardiac金劇 hypertrophy were observed, de近暗monstrating immune-targeting and deple路車tion of activated cardiac fibroblasts i喝音s possible. However, since an黑金y effective treatment woul關電d need to target endogenou日白s proteins specifically expres不懂sed on cardiac fibroblasts,兒一 gene-expression data from human heart 年水samples was analysed to id快錯entify fibroblast-specif腦小ic genes upregulated i件東n the myocardium of patients with ei道光ther hypertrophic c花鄉ardiomyopathy (HCM) o不電r dilated cardiomyopat銀行hy (DCM). To this end, the cell-地唱surface glycoprotein FAP (8) wa火機s identified by immunostaining as 議放a target and shown to be specificall吃遠y upregulated following cardia木業c injury. Using the 校問above AngII/PE model, retr訊又oviral transduc空們ed “FAP’’ CAR T cell頻我s were administered, and hearts我店 analysed after 4 and技術 8 weeks. In both 喝湖cases, there was a clear reduction in f花歌ibrosis and a partial rescu妹嗎e of both systol做廠ic and diastolic cardiac functi理現on in injured mi紙關ce treated with FAP CAR T cell弟草s compared to co化外ntrols.

In summary, this work rev文朋eals a proof-of-co地廠ncept for the possibility of 文好using engineered T cells t國去o target and treat a 呢你disease state other than cancer, namel舊亮y cardiac fibrosis. While no obvious in空亮creases in cytokine levels, 電鐘myocardial toxicity or inflam校雨matory markers were observed, m分少uch work is still中朋 necessary before this appro聽美ach can be trans山姐lated into humans去黃. Further, while reducing fibrosis in 用女models of myocardial disease ha服鐵s previously been 吃睡shown to reduce fibrosis an喝件d improve function in mice (7,9), we道商 are still left with the 輛計problem that the adult human heart c窗朋annot regenerate due to 師很a lack of cardiomyocyte proliferation.

VectorBuilder

VectorBuilder offer吃弟s a wide range of vir大地us packaging option東可s, including MSCV, lentivirus, AA裡從V, adenovirus and MMLV; 分明all available for both in vitro and 這離in vivo applications. 工見Use our online platform 業金to design and order custom vectors 筆西specific to your research n文亮eeds. VectorBuilder also offers B很家AC recombination,員線 custom stable c雜來ell lines and shRNA/CRISPR libraries內作, all at low cost and舊讀 with fast turnaround, allowin鐵著g you to focus on your ex理他periments instead of making reagen頻笑ts.

References

1. Poss KD, et al. Heart regeneration i日城n zebrafish. Science. 2002; 298:2188–2190.
2. Porrello ER, et al. Transient regene坐都rative potential of t她化he neonatal mouse hear飛報t. Science. 2011; 331:1078他匠–1080.
3. Kikuchi K, et al. Primary contribution to zebrafish h小技eart regeneration b章機y gata4+ cardiomyocyt草鐵es. Nature. 2010; 鐵去464:601–605.
4. Jopling C, et al. Zebrafish heart regeneration oc鄉購curs by cardiomyocyte ded西劇ifferentiation and proliferation. Nature. 2010; 464:606–白術609.
5. Aghajanian H, et al. Targeting cardiac fibro飛自sis with engineered T cells. Nature. 2019; 573: 430火跳–433.
6. June, C. H, et al. CAR T cell immunother腦就apy for human cancer. Science. 2018; 359: 1361–1365.
7. Kaur, H., et al.亮光 Targeted Ablation of 請低Periostin-Expressing Activated Fibrobla她算sts Prevents Adverse慢問 Cardiac Remodeling in Mice. Circulation research. 2016; 118: 1分費906–1917.
8. Scanlan, M. J., et al. Molecular cloning of fibroblast activa吃窗tion protein alpha土藍, a member of the serine protea藍音se family selectively exp你日ressed in stromal fibroblasts of 業那epithelial cancers. Clinical Genetic. 2012; 82(頻開4):367-73.
9. Kanisicak, O., et al. Genetic lineage traci購資ng defines myofibroblast or哥事igin and function 風熱in the injured heart. Nature Communication. 輛金2016; 7: 12260.