Brain-derived neurotrophic factor promotes immune reconstitution following radiation injury via activation of bone marrow mesenchymal stem cells.
Brain-derived neurotrophic factor promotes immune reconstitution following radiation injury via activation of bone marrow mesenchymal stem cells.
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DOI：
10.1371/journal.pone.0259042
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Himburg HA
中科院分区：
文献类型：
--
作者：
Sharma GP;Frei AC;Narayanan J;Gasperetti T;Veley D;Amjad A;Albano K;Fish BL;Himburg HA
脑源性神经营养因子（Brain-derived neurotrophic factor，BDNF）是神经生长因子家族的一员，其在神经发育、长时记忆、脑损伤和神经退行性疾病中的作用已被广泛研究。BDNF信号通过原肌球蛋白受体激酶B（Trk B）刺激神经元细胞存活。出于这个原因，小分子TrkB激动剂处于临床前开发中，用于治疗一系列神经退行性疾病和损伤。我们实验室最近报道BDNF由促再生内皮祖细胞（EPCs）分泌，其支持全身照射（TBI）后的造血重建。在这里，我们报告BDNF-TrkB信号在辐射损伤后骨髓和胸腺再生中发挥新的再生作用。骨髓抑制性辐射损伤后外源性给予BDNF或TrkB激动剂7，8-二羟基黄酮（7，8-DHF）促进了成熟血细胞和能够多谱系重建的造血干细胞的更快恢复。BDNF通过激活PDGFRα+骨髓间充质干细胞（MSC）促进造血再生，PDGFRα+骨髓间充质干细胞（MSC）增加造血细胞因子白细胞介素6（IL-6）和白血病抑制因子（LIF）的分泌，以响应TrkB激活。这些数据表明，用BDNF或7，8-DHF药理学激活BDNF通路可能有益于治疗放疗或化疗诱导的骨髓抑制。
Brain-derived neurotrophic factor (BDNF) is a member of the nerve growth factor family which has been extensively studied for its roles in neural development, long-term memory, brain injury, and neurodegenerative diseases. BDNF signaling through tropomyosin receptor kinase B (TrkB) stimulates neuronal cell survival. For this reason, small molecule TrkB agonists are under pre-clinical develoment for the treatment of a range of neurodegenerative diseases and injuries. Our laboratory recently reported BDNF is secreted by pro-regenerative endothelial progenitor cells (EPCs) which support hematopoietic reconstitution following total body irradiation (TBI). Here we report BDNF-TrkB signaling plays a novel regenerative role in bone marrow and thymic regeneration following radiation injury. Exogenous administration of BDNF or TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) following myelosuppressive radiation injury promoted faster recovery of mature blood cells and hematopoietic stem cells capable of multi-lineage reconstitution. BDNF promotes hematopoietic regeneration via activation of PDGFRα+ bone marrow mesenchymal stem cells (MSCs) which increase secretion of hematopoietic cytokines interleukin 6 (IL-6) and leukemia inhibitory factor (LIF) in response to TrkB activation. These data suggest pharmacologic activation of the BDNF pathway with either BDNF or 7,8-DHF may be beneficial for treatment of radiation or chemotherapy induced myelosuppression.
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