RATIONALE The chronic lung disease bronchopulmonary dysplasia (BPD) remains the most common complication of extreme prematurity (<28 weeks of gestation). Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) represent an opportunity for autologous cell-therapy, as UC-MSCs have been shown to improve lung function and structure in experimental BPD. However, characterization and repair capacity of UC-MSCs derived from donors with pregnancy-related complications associated with prematurity remain unexplored. OBJECTIVES To characterize UC-MSCs' transcriptome and determine if pregnancy-related complications (preeclampsia and chorioamnionitis) alter their therapeutic potential. METHODS Single-cell RNA sequencing (scRNA-seq) was used to compare the transcriptome of UC-MSCs derived from five term donors, 16 preterm donors, and human neonatal dermal fibroblasts (HNDFs, control cells of mesenchymal origin), and correlated with their therapeutic potential in experimental BPD. Using publicly available neonatal lung single-nuclei RNA sequencing data, we also determined putative communication networks between UC-MSCs and resident lung cell populations. MEASUREMENTS AND MAIN RESULTS Most UC-MSCs displayed a similar transcriptome despite of their pregnancy-related conditions and mitigated hyperoxia-induced lung injury in newborn rats. Conversely, HNDFs, one term and two preeclampsia preterm UC-MSC donors exhibited a distinct transcriptome enriched in genes related to fibroblast function and senescence and were devoid of therapeutic benefit in hyperoxia-induced BPD. Conversely, therapeutic UC-MSCs displayed a unique transcriptome active in cell proliferation and distinct cell-cell interactions with neonatal lung cell populations, including NEGR and NRNX pathways. CONCLUSION Term and preterm UC-MSCs are lung protective in experimental BPD. scRNA-seq allows to identify donors with a distinct UC-MSC transcriptome characteristic of reduced therapeutic potential.

中文翻译：

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单细胞 RNA 测序指导自体早产脐带间充质细胞疗法。


基本原理 慢性肺病支气管肺发育不良 （BPD） 仍然是极度早早产 （x3C28 妊娠周） 最常见的并发症。脐带来源的间充质基质细胞 （UC-MSC） 代表了自体细胞疗法的机会，因为 UC-MSC 已被证明可以改善实验性 BPD 中的肺功能和结构。然而，来自与早产相关的妊娠相关并发症的供体的 UC-MSC 的表征和修复能力仍未得到探索。目的 表征 UC-MSCs 的转录组并确定妊娠相关并发症 （子痫前期和绒毛膜羊膜炎） 是否会改变其治疗潜力。方法 采用单细胞 RNA 测序 （scRNA-seq） 比较来源于 5 名足月供体、16 名早产供体和人新生儿真皮成纤维细胞 （HNDFs，间充质来源的对照细胞） 的 UC-MSCs 转录组，并与它们在实验性 BPD 中的治疗潜力相关。使用公开可用的新生儿肺单核 RNA 测序数据，我们还确定了 UC-MSC 和常驻肺细胞群之间的推定通信网络。测量和主要结果大多数 UC-MSC 显示出相似的转录组，尽管它们与妊娠相关，并减轻了高氧诱导的新生大鼠肺损伤。相反，HNDFs、1 足月和 2 例子痫前期早产 UC-MSC 供体表现出独特的转录组，富含与成纤维细胞功能和衰老相关的基因，并且在高氧诱导的 BPD 中缺乏治疗益处。相反，治疗性 UC-MSCs 在细胞增殖中表现出独特的转录组活性，并且与新生儿肺细胞群（包括 NEGR 和 NRNX 通路）具有不同的细胞间相互作用。 结论足月和早产 UC-MSCs 在实验性 BPD 中具有肺保护作用。scRNA-seq 允许识别具有治疗潜力降低的独特 UC-MSC 转录组特征的供体。