Salivary gland precursor cells

描述（由申请人提供）：唾液腺对口腔健康至关重要，正常功能的丧失会导致受影响患者的不良继发性疾病。用于治疗头颈部癌症以及自身免疫性疾病的放射疗法对唾液腺，特别是对主要负责唾液分泌的腺泡细胞造成不可逆的损伤。目前治疗涎腺功能障碍的方法是姑息性和短期的。永久恢复腺体功能的潜在策略包括细胞置换。虽然有证据表明唾液腺有干细胞，但它们还没有被分离出来。此外，干细胞对唾液腺维持的贡献程度尚不清楚，因为据报道，在成人中，腺泡细胞通过自我复制更新。我们已经鉴定了以Ascl3表达为标志的唾液腺祖细胞。谱系追踪显示，这些祖细胞产生导管细胞和腺泡细胞的子集，但不是大多数的浆液性腺泡细胞在下颌下腺和腮腺。我们提出，Ascl3表达细胞，位于导管，是短暂的中间祖细胞参与唾液腺的维护。由于大多数的浆液性腺泡细胞在下颌下腺和腮腺不是来自Ascl3表达细胞，我们假设，浆液性腺泡细胞指定由一个单独的独特的祖细胞群体。该建议将建立唾液腺祖细胞的分化潜能，并研究这些细胞促进萎缩腺再生的能力。我们有三个具体目标：（1）检查表达Ascl3的祖细胞有助于唾液腺的维持和再生的潜力。(2)确定严重的腺泡祖细胞在唾液腺中的作用。(3)检测培养的祖细胞在移植后促进唾液腺再生的能力。唾液腺中祖细胞类型的鉴定和表征是细胞替代疗法的关键步骤。 公共卫生相关性：唾液腺功能会因头颈部癌症的放射治疗、药物治疗和自身免疫性疾病（如干燥综合征）而显著降低。这对受影响患者的口腔健康有重大影响。可能的永久性治疗方法包括将细胞移植到受损的腺体中。这项建议将检查唾液腺祖细胞的能力，有助于腺体修复移植后。

DESCRIPTION (provided by applicant): Salivary glands are critical for oral health, and loss of normal function results in adverse secondary conditions in affected patients. Radiation therapy, used to treat head and neck cancers, as well as autoimmune diseases, cause irreversible damage to the salivary glands, specifically to the acinar cells primarily responsible for salivary secretion. Current therapies for salivary gland dysfunction are pallative and short term. Potential strategies for permanent restoration of gland function include cell replacement. Although evidence suggests that salivary glands have stem cells, they have not yet been isolated. Moreover, the extent of stem cell contribution to salivary gland maintenance is unclear, as it is also reported that, in adults, acinar cells are renewed by self-duplication. We have identified a salivary gland progenitor cell that is marked by expression of Ascl3. Lineage tracing shows that these progenitors generate duct cells and a subset of acinar cells, but not the majority of serous acinar cells in the submandibular and parotid glands. We propose that Ascl3-expressing cells, located in the ducts, are transient intermediate progenitor cells involved in salivary gland maintenance. As the majority of serous acinar cells in the submandibular and parotid glands are not derived from Ascl3- expressing cells, we hypothesize that serous acinar cells are specified by a separate distinct progenitor population. This proposal will establish the differentiation potential of salivary gland progenitor cells and investigate the ability of these cells to contribute to regeneration of an atrophic gland. We have three specific aims: (1) To examine the potential of Ascl3-expressing progenitor cells to contribute to the maintenance and regeneration of the salivary gland. (2) To determine the role of serious acinar progenitors in the salivary gland. (3) To test the ability of cultured progenitor cells to contribute to salivary gland regeneration following transplantation. The identification and characterization of progenitor cell types in the salivary gland is a critical step in the path to cell replacement therapies. PUBLIC HEALTH RELEVANCE: Salivary gland function is dramatically reduced by radiation treatment for head and neck cancers, by drug therapy and in autoimmune diseases such as Sjogren's syndrome. This has a significant impact on the oral health of affected patients. Possible permanent cures include cell transplantation into the damaged gland. This proposal will examine the ability of salivary gland progenitor cells to contribute to gland repair following transplantation.