Detection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts.
Detection of infiltrating fibroblasts by single-cell transcriptomics in human kidney allografts.
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DOI：
10.1371/journal.pone.0267704
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Muthukumar, Thangamani
中科院分区：
文献类型：
--
作者：
Suryawanshi, Hemant;Yang, Hua;Lubetzky, Michelle;Morozov, Pavel;Lagman, Mila;Thareja, Gaurav;Alonso, Alicia;Li, Carol;Snopkowski, Catherine;Belkadi, Aziz;Mueller, Franco B.;Lee, John R.;Dadhania, Darshana M.;Salvatore, Steven P.;Seshan, Surya, V;Sharma, Vijay K.;Suhre, Karsten;Suthanthiran, Manikkam;Tuschl, Thomas;Muthukumar, Thangamani
我们测试了一个假设，即人类肾移植活检的单细胞RNA测序（scRNA-seq）分析将揭示不同的细胞类型和状态，并产生见解，以破译同种免疫损伤的复杂异质性。我们选择了来自3个个体的3个肾皮质活检组织用于scRNA-seq，并在10 x Chromium平台上使用相同的方案新鲜处理它们;（i）HK：来自活体供体的天然肾活检组织，（ii）AKl：具有移植肾小球病、肾小管间质纤维化和移植物功能恶化的同种异体移植肾，和（iii）AK 2：成功治疗主动抗体介导的排斥反应后的同种异体移植肾。我们没有研究T细胞介导的排斥反应。我们产生了7217个高质量的单细胞转录组。利用X和Y染色体常染色体基因表达所揭示的供体-供体性别错配，我们确定在移植后42个月的AK 1伴纤维化中，超过一半的肾同种异体移植成纤维细胞是供体来源的，因此可能是迁移和移植物浸润性的，而在移植后84个月的AK 2无纤维化中，大多数成纤维细胞是供体器官来源的。此外，AK 1富含过度表达促纤维化细胞外基质基因的肾小管祖细胞。在成功治疗排斥反应后8个月，AK 2含有高表达免疫球蛋白的浆母细胞、T细胞趋化因子的内皮细胞加工和细胞毒性T细胞的持续存在。除了这些关键发现外，我们的分析还揭示了肾脏中独特的细胞类型和状态。总之，单细胞转录组学产生了新的机制见解，这可能为移植受者的个性化护理铺平道路。
We tested the hypothesis that single-cell RNA-sequencing (scRNA-seq) analysis of human kidney allograft biopsies will reveal distinct cell types and states and yield insights to decipher the complex heterogeneity of alloimmune injury. We selected 3 biopsies of kidney cortex from 3 individuals for scRNA-seq and processed them fresh using an identical protocol on the 10x Chromium platform; (i) HK: native kidney biopsy from a living donor, (ii) AK1: allograft kidney with transplant glomerulopathy, tubulointerstitial fibrosis, and worsening graft function, and (iii) AK2: allograft kidney after successful treatment of active antibody-mediated rejection. We did not study T-cell-mediated rejections. We generated 7217 high-quality single cell transcriptomes. Taking advantage of the recipient-donor sex mismatches revealed by X and Y chromosome autosomal gene expression, we determined that in AK1 with fibrosis, 42 months after transplantation, more than half of the kidney allograft fibroblasts were recipient-derived and therefore likely migratory and graft infiltrative, whereas in AK2 without fibrosis, 84 months after transplantation, most fibroblasts were donor-organ-derived. Furthermore, AK1 was enriched for tubular progenitor cells overexpressing profibrotic extracellular matrix genes. AK2, eight months after successful treatment of rejection, contained plasmablast cells with high expression of immunoglobulins, endothelial cell elaboration of T cell chemoattractant cytokines, and persistent presence of cytotoxic T cells. In addition to these key findings, our analysis revealed unique cell types and states in the kidney. Altogether, single-cell transcriptomics yielded novel mechanistic insights, which could pave the way for individualizing the care of transplant recipients.
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