Astrocyte progenitor transplantation promotes regeneration of bulbospinal respiratory axons, recovery of diaphragm function, and a reduced macrophage response following cervical spinal cord injury
Astrocyte progenitor transplantation promotes regeneration of bulbospinal respiratory axons, recovery of diaphragm function, and a reduced macrophage response following cervical spinal cord injury
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DOI：
10.1002/glia.23555
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发表时间：
2019-03-01
期刊：
影响因子：
6.2
通讯作者：
Lepore, Angelo C.
中科院分区：
文献类型：
--
作者：
Goulao, Miguel;Ghosh, Biswarup;Lepore, Angelo C.
干细胞/祖细胞移植移植星形胶质细胞是治疗脊髓损伤的一种潜在的有效策略。自发发生的或对实验操作有反应的轴突延伸到SCI损伤中通常是沿着内源性星形胶质细胞“桥”观察到的，这表明通过星形胶质细胞谱系移植增强这种反应可以促进轴突再生。鉴于脊髓损伤后呼吸功能障碍的重要性，我们将胶质限制性前体细胞(GRPs)--一类谱系受限的星形胶质细胞前体细胞--移植到C2半横断模型中，并评估了其对横隔膜功能和支配膈运动神经元(PhMN)的下行头端腹侧呼吸群(RVRG)轴突的生长反应的影响。GRPs能在损伤脊髓内长期存活，并能有效分化为星形胶质细胞。GRPs可显著恢复横隔肌肌电波幅，并刺激受损rVRG轴突的再生。尽管rVRG纤维穿过损伤，但没有再生轴突重新进入尾侧脊髓来重新支配PhMN，这表明这种再生反应-尽管令人印象深刻-并不是恢复的原因。在同侧C3-5腹角(PhMN部位)，GRPs可诱导对侧rVRG和5-羟色胺(5-HT)轴突的备用纤维大量萌发，这种发芽对调节PhMN的兴奋性很重要；这种萌发可能参与了GRPs的功能效应。最后，GRPs降低了巨噬细胞的反应(在诱导轴突收缩和限制再生中起关键作用)，包括在半横断内和围绕PhMN的完整的尾侧脊髓。这些发现表明，星形胶质细胞前体移植可显著促进rVRG-PhMN回路的可塑性和横隔膜功能的恢复，并提示这些作用可能部分是通过免疫调节实现的。
Stem/progenitor cell transplantation delivery of astrocytes is a potentially powerful strategy for spinal cord injury (SCI). Axon extension into SCI lesions that occur spontaneously or in response to experimental manipulations is often observed along endogenous astrocyte "bridges," suggesting that augmenting this response via astrocyte lineage transplantation can enhance axon regrowth. Given the importance of respiratory dysfunction post-SCI, we transplanted glial-restricted precursors (GRPs)-a class of lineage-restricted astrocyte progenitors-into the C2 hemisection model and evaluated effects on diaphragm function and the growth response of descending rostral ventral respiratory group (rVRG) axons that innervate phrenic motor neurons (PhMNs). GRPs survived long term and efficiently differentiated into astrocytes in injured spinal cord. GRPs promoted significant recovery of diaphragm electromyography amplitudes and stimulated robust regeneration of injured rVRG axons. Although rVRG fibers extended across the lesion, no regrowing axons re-entered caudal spinal cord to reinnervate PhMNs, suggesting that this regeneration response-although impressive-was not responsible for recovery. Within ipsilateral C3-5 ventral horn (PhMN location), GRPs induced substantial sprouting of spared fibers originating in contralateral rVRG and 5-HT axons that are important for regulating PhMN excitability; this sprouting was likely involved in functional effects of GRPs. Finally, GRPs reduced the macrophage response (which plays a key role in inducing axon retraction and limiting regrowth) both within the hemisection and at intact caudal spinal cord surrounding PhMNs. These findings demonstrate that astrocyte progenitor transplantation promotes significant plasticity of rVRG-PhMN circuitry and restoration of diaphragm function and suggest that these effects may be in part through immunomodulation.