IL6 Related Cytokines Augment Angiogenesis in Nascent and Mature Human Endothelium Via JAK2 Signaling

While therapeutic angiogenesis holds promise for vascular diseases, progress has been limited due to discrepancies in defining adult endothelial progenitors. We have identified and characterized a population of pluripotent derived NRP1+CD34+ nascent endothelial cells, immediately diverged from NRP1+CD34- mesodermal cells. We contrasted the transcriptional profile of NRP1+ CD34+ nascent endothelial cells against undifferentiated human pluripotent stem cells and human umbilical vein endothelial cells (HUVECs) to gain insights into the pathways that are uniquely activated in formation of new endothelium. We found significant upregulation of IL-6 related growth factor receptors, including ciliary neurotrophic factor receptor (CNTFR), and their downstream JAK/STAT signaling components in NRP1+CD34+ endothelial cells. When exposed to CNTF, angiogenic sprouting of NRP1+CD34+ was induced in Matrigel, which was abolished with JAK2 inhibition. Furthermore, we found evidence of JAK2 dependent cytokine signaling in more mature endothelium, highlighting the significance of the IL6R/JAK2 pathway, well known in hematopoiesis, in vascular biology. The findings identify a novel group of growth factor receptors and downstream signaling components that may be targeted to modulate angiogenesis and vasculogenesis. 7 samples analyzed, 2 replicates for NRP1+CD34+, 3 replicates for NRP1+CD34-

尽管治疗性血管生成（therapeutic angiogenesis）在血管疾病的治疗中颇具应用前景，但由于成体内皮祖细胞（adult endothelial progenitors）的定义尚存争议，相关研究进展始终受限。本研究鉴定并表征了一群多能干细胞衍生的NRP1+CD34+新生内皮细胞，该细胞群直接从NRP1+CD34-中胚层细胞分化而来。我们将NRP1+CD34+新生内皮细胞的转录谱与未分化人多能干细胞、人脐静脉内皮细胞（human umbilical vein endothelial cells, HUVECs）进行对比，以剖析新血管内皮形成过程中被特异性激活的信号通路。研究结果显示，NRP1+CD34+内皮细胞中IL-6相关生长因子受体——包括睫状神经营养因子受体（ciliary neurotrophic factor receptor, CNTFR）——及其下游JAK/STAT信号通路组分存在显著上调。当暴露于CNTF时，NRP1+CD34+细胞的血管出芽生成可在基质胶（Matrigel）中被诱导，而该效应可通过JAK2抑制被完全阻断。此外，我们在更为成熟的内皮细胞中发现了JAK2依赖性细胞因子信号转导的相关证据，这凸显了在造血过程中已被广泛认知的IL6R/JAK2通路在血管生物学中的关键作用。本研究鉴定出一类新型生长因子受体及下游信号通路组分，有望成为调控血管生成与血管发生的潜在干预靶点。本次研究共分析7份样本，其中NRP1+CD34+组设置2次生物学重复，NRP1+CD34-组设置3次生物学重复。