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患者不良的继发性疾病。用于治疗头颈部癌症以及自身免疫性疾病的放射疗法会对唾液腺造成不可逆转的损伤，特别是对主要负责唾液分泌的腺泡细胞。目前治疗唾液腺功能障碍的方法是姑息性的和短期的。永久性恢复腺体功能的潜在策略包括细胞替换。虽然证据表明唾液腺有干细胞，但它们尚未被分离出来。此外，干细胞对唾液腺维持的贡献程度尚不清楚，因为也有报道称，在成人中，腺泡细胞通过自我复制进行更新。我们已经鉴定出以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一部分腺泡细胞，但不是颌下腺和腮腺的大多数浆液腺泡细胞。我们认为，位于腺管中的表达ascl3的细胞是参与唾液腺维持的瞬时中间祖细胞。由于颌下腺和腮腺中的大多数浆液性腺泡细胞不是来自表达Ascl3的细胞，我们假设浆液性腺泡细胞是由一个单独的不同的祖细胞群指定的。本研究将建立唾液腺祖细胞的分化潜能，并探讨这些细胞对萎缩性腺体再生的作用。我们有三个具体目的：(1)研究表达ascl3的祖细胞在维持和再生唾液腺中的潜力。(2)确定严重腺泡祖细胞在唾液腺中的作用。(3)检测培养的祖细胞对移植后唾液腺再生的促进作用。唾液腺祖细胞类型的鉴定和表征是细胞替代疗法的关键一步。

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.