Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel.
Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel.
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DOI：
10.1126/sciadv.adc8753
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发表时间：
2022-12-21
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
作者：
头颈癌放疗后唾液腺腺泡细胞严重衰竭，导致唾液流失和广泛的口腔消化并发症。由于没有再生疗法，器官功能障碍是不可逆转的。在这里，使用成年小鼠系统，我们证明放射损伤的唾液腺可以通过持续递送神经源性毒蕈碱受体激动剂西维美林功能再生。我们发现，内源性腺体修复与神经活动和腺泡细胞分裂的增加相一致，这仅限于放射后的第一周，随后发生广泛的腺泡细胞变性、功能障碍和胆碱能失神经支配。然而，我们发现通过持续局部递送西维美林-海藻酸盐水凝胶来模拟胆碱能毒蕈碱输入足以再生神经支配的腺泡，并在长期（约3个月）内将生理唾液分泌保持在非辐照水平。因此，我们揭示了一种以前未知的再生方法来恢复上皮器官的结构和功能，这对人类患者具有广泛的意义。一种可注射的神经源性水凝胶可以恢复受辐射损伤的唾液组织的结构和功能。
Salivary gland acinar cells are severely depleted after radiotherapy for head and neck cancer, leading to loss of saliva and extensive oro-digestive complications. With no regenerative therapies available, organ dysfunction is irreversible. Here, using the adult murine system, we demonstrate that radiation-damaged salivary glands can be functionally regenerated via sustained delivery of the neurogenic muscarinic receptor agonist cevimeline. We show that endogenous gland repair coincides with increased nerve activity and acinar cell division that is limited to the first week after radiation, with extensive acinar cell degeneration, dysfunction, and cholinergic denervation occurring thereafter. However, we found that mimicking cholinergic muscarinic input via sustained local delivery of a cevimeline–alginate hydrogel was sufficient to regenerate innervated acini and retain physiological saliva secretion at nonirradiated levels over the long term (>3 months). Thus, we reveal a previously unknown regenerative approach for restoring epithelial organ structure and function that has extensive implications for human patients. An injectable neurogenic hydrogel restores the structure and function of radiation-damaged salivary tissue.
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