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Abstract：
Chemoradiotherapy (CRT) and radiotherapy (RT) have served as anticancer treatments and neoadjuvant therapies for conquering multimodal rectal cancers including colorectal carcinoma (CRC), yet the concomitant radiation-induced colorectal fibrosis (RICF) has caused chronic toxicity and stenosis in the colorectal mucosa of patients. Mesenchymal stem/stromal cells (MSCs) with unique bidirectional immunoregulation and anti-fibrotic effect have been recognized as splendid sources for regenerative purposes including intestinal diseases. Herein, we are aiming to verify the feasibility and variations of MSC-based cytotherapy for the remission of RICF from the pathological features and the potential impact upon the transcriptomic signatures of RICF rats. For the purpose, we utilized our well-established RICF Sprague-Dawley (SD) rats by radiation for five weeks, and conducted consecutive intraperitoneal injection of two distinct MSCs for treatment, including MSCs derived from adult adipose tissue (AD-MSCs) and perinatal umbilical cord (UC-MSCs). On the one hand, the efficacy of AD-MSCs and UC-MSCs was assessed by diverse indicators, including weight change, pathological detections (e.g., H&E staining, Masson staining, EVG staining, IF staining, and IHC staining), and proinflammatory and fibrotic factor expression. On the other hand, we turned to RNA-sequencing (RNA-SEQ) and multifaceted bioinformatics analyses (e.g., GOBP, Venn Map, KEGG, and GSEA) to compare the impact of AD-MSC and UC-MSC treatment upon the gene expression profiling and genetic variations. RICF rats after consecutive AD-MSC and UC-MSC administration revealed comparable remission in histopathogenic features and significant suppression of diverse proinflammatory and fibrotic factors expression. Meanwhile, RICF rats after both MSC treatment revealed decrease and variations in the alterations in diverse gene expression and somatic mutations compared to RICF rats. Collectively, our data indicated the comparable therapeutic effect of AD-MSCs and UC-MSCs upon RICF in SD rats, together with the conservations in gene expression profiling and the diverse variations in genetic mutations. Our findings indicated the multifaceted impact of MSC infusion for the supervision of RICF both at the therapeutic and transcriptomic levels, which would provide novel references for the further evaluation and development of MSC-based regimens in future.
摘要：
放化疗（CRT）和放疗（RT）已作为抗癌治疗和新辅助疗法，用于治疗包括结直肠癌（CRC）在内的多模态直肠癌。然而,伴随的放射诱导的结直肠纤维化(RICF)已导致患者结直肠粘膜的慢性毒性和狭窄.具有独特的双向免疫调节和抗纤维化作用的间充质干细胞/基质细胞（MSC）已被认为是用于包括肠道疾病在内的再生目的的出色来源。在这里，我们的目标是验证基于MSC的细胞疗法从病理特征中缓解RICF的可行性和变异,以及对RICF大鼠转录组特征的潜在影响.出于目的,我们利用我们建立良好的RICFSprague-Dawley（SD）大鼠进行辐射五周，并连续腹膜内注射两种不同的MSCs进行治疗，包括来源于成人脂肪组织的MSCs(AD-MSCs)和围产期脐带MSCs(UC-MSCs)。一方面,通过多种指标评估AD-MSCs和UC-MSCs的疗效，包括体重变化,病理检测(例如，H&E染色,Masson染色,EVG染色,IF染色,和IHC染色），和促炎和纤维化因子的表达。另一方面,我们转向RNA测序(RNA-SEQ)和多方面的生物信息学分析(例如，GOBP,维恩地图,KEGG,和GSEA），以比较AD-MSC和UC-MSC治疗对基因表达谱和遗传变异的影响。连续施用AD-MSC和UC-MSC后，RICF大鼠在组织病理学特征方面表现出相当的缓解，并显着抑制了多种促炎和纤维化因子的表达。同时,与RICF大鼠相比，两种MSC治疗后的RICF大鼠均显示出不同基因表达和体细胞突变的减少和变化。总的来说，我们的数据表明AD-MSCs和UC-MSCs对SD大鼠RICF的治疗效果相当，以及基因表达谱的保守和基因突变的不同变化。我们的研究结果表明，MSC输注在治疗和转录组水平上对RICF的监督具有多方面的影响。这将为将来基于MSC的方案的进一步评估和开发提供新的参考。
