Human amnion epithelial cells rescue cell death via immunomodulation of microglia in a mouse model of perinatal brain injury.
Human amnion epithelial cells rescue cell death via immunomodulation of microglia in a mouse model of perinatal brain injury.
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在围产期脑损伤小鼠模型中，人羊膜上皮细胞通过小胶质细胞的免疫调节来挽救细胞死亡。
DOI：
10.1186/s13287-017-0496-3
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发表时间：
2017-02-28
影响因子：
7.5
通讯作者：
Tolcos M
中科院分区：
文献类型：
--
作者：
Leaw B;Zhu D;Tan J;Muljadi R;Saad MI;Mockler JC;Wallace EM;Lim R;Tolcos M
人羊膜上皮细胞 (hAEC) 具有克隆形成能力，可减少炎症引起的组织损伤。免疫反应的扰动与围产期脑损伤的发病机制有关；因此，调节这种反应可能是治疗或预防此类损伤的新疗法。 hAEC 的免疫调节特性已在其他动物模型中得到证实，但尚未对损伤后对脑免疫细胞的影响进行详细研究。在这里，我们研究了 hAEC 对小胶质细胞的影响，小胶质细胞是大脑损伤的第一个免疫反应者。我们建立了一个结合新生儿炎症和围产期高氧的小鼠模型，这两者都是与围产期脑损伤相关的危险因素。在胚胎第 16 天，我们对 C57Bl/6 J 幼鼠进行羊膜内注射脂多糖 (LPS) 或盐水（对照）。出生后第 0 天 (P)，LPS 幼崽被置于高氧环境（65% 氧气），而对照幼崽则置于常氧环境中 14 天。在 P4 时，对幼崽进行静脉注射 hAEC 或生理盐水。在 P14 时，相对于对照组，LPS 和高氧幼鼠体重减轻，皮层、纹状体和白质中的凋亡细胞 (TUNEL)、白质中的星形胶质细胞 (GFAP) 以及皮层和纹状体中的活化小胶质细胞 (CD68) 密度增加，但总小胶质细胞密度 (Iba1) 没有变化。 hAEC 给药挽救了体重减轻、白质中细胞凋亡和星形胶质细胞面积覆盖的减少，但增加了总小胶质细胞和活化小胶质细胞的密度。然后，我们用 LPS 刺激原代小胶质细胞 (CD45lowCD11b+) 24 小时，然后与 hAEC 条件培养基共培养 48 小时。 hAEC 条件培养基增加小胶质细胞吞噬活性，减少小胶质细胞凋亡并减少 M1 激活标记物 (CD86)。用 LPS 刺激 hAEC 24 小时不会改变已知调节小胶质细胞活性的细胞因子的释放。这些数据表明 hAEC 可能通过释放营养因子来直接免疫调节脑小胶质细胞。这一观察结果表明 hAEC 可能在围产期脑损伤的治疗中发挥作用。
Human amnion epithelial cells (hAECs) are clonogenic and have been proposed to reduce inflammatory-induced tissue injury. Perturbation of the immune response is implicated in the pathogenesis of perinatal brain injury; modulating this response could thus be a novel therapy for treating or preventing such injury. The immunomodulatory properties of hAECs have been shown in other animal models, but a detailed investigation of the effects on brain immune cells following injury has not been undertaken. Here, we investigate the effects of hAECs on microglia, the first immune responders to injury within the brain. We generated a mouse model combining neonatal inflammation and perinatal hyperoxia, both of which are risk factors associated with perinatal brain injury. On embryonic day 16 we administered lipopolysaccharide (LPS), or saline (control), intra-amniotically to C57Bl/6 J mouse pups. On postnatal day (P)0, LPS pups were placed in hyperoxia (65% oxygen) and control pups in normoxia for 14 days. Pups were given either hAECs or saline intravenously on P4. At P14, relative to controls, LPS and hyperoxia pups had reduced body weight, increased density of apoptotic cells (TUNEL) in the cortex, striatum and white matter, astrocytes (GFAP) in the white matter and activated microglia (CD68) in the cortex and striatum, but no change in total microglia density (Iba1). hAEC administration rescued the decreased body weight and reduced apoptosis and astrocyte areal coverage in the white matter, but increased the density of total and activated microglia. We then stimulated primary microglia (CD45lowCD11b+) with LPS for 24 h, followed by co-culture with hAEC conditioned medium for 48 h. hAEC conditioned medium increased microglial phagocytic activity, decreased microglia apoptosis and decreased M1 activation markers (CD86). Stimulating hAECs for 24 h with LPS did not alter release of cytokines known to modulate microglia activity. These data demonstrate that hAECs can directly immunomodulate brain microglia, probably via release of trophic factors. This observation offers promise that hAECs may afford therapeutic utility in the management of perinatal brain injury.