ECTOPIC TGF-BETA-1 EXPRESSION IN THE SECRETORY MAMMARY EPITHELIUM INDUCES EARLY SENESCENCE OF THE EPITHELIAL STEM-CELL POPULATION
ECTOPIC TGF-BETA-1 EXPRESSION IN THE SECRETORY MAMMARY EPITHELIUM INDUCES EARLY SENESCENCE OF THE EPITHELIAL STEM-CELL POPULATION
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DOI：
10.1006/dbio.1995.1060
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发表时间：
1995-03-01
影响因子：
2.7
通讯作者：
SMITH, GH
中科院分区：
文献类型：
--
作者：
KORDON, EC;MCKNIGHT, RA;SMITH, GH
乳腺的一个重要特征是其上皮的再生能力，这在连续的哺乳和退化周期中得到证明。表达乳清酸性蛋白（WAP）启动子驱动的转化生长因子β 1（TGF β 1）cDNA的妊娠小鼠不能产生分泌性乳腺上皮或乳酸。在这里，我们调查是否异位TGF β 1诱导这种表型通过影响转基因上皮细胞直接或trans. Reciprocal移植正常和转基因宿主之间的乳腺组织导致在相同的乳腺脂肪垫内的移植物的相应表型的发展。当从两者分离的乳腺上皮细胞在植入前混合，使转基因和正常上皮细胞将一起更早地发育时，在所得嵌合乳腺增生中同时观察到两种表型。由于没有反式效应是可检测的，我们假设，早期表达的转基因结果受损的小叶祖细胞通过内分泌机制。与此一致，WAP启动子驱动的蛋白质表达在发情期未成熟雌性对向导管的单个细胞中检测到。将WAP-TGF β 1乳腺移植到非妊娠宿主中显示，转基因植入物，即使是来自年轻青春期后处女女性的植入物，重新填充无上皮乳腺脂肪垫的能力减弱。因此，WAP-TGF β 1的异位表达不仅损害小叶祖细胞，而且促进乳腺导管上皮再生能力的早期衰老。这使我们提出，乳腺上皮干细胞在乳腺上皮中产生两种功能不同的祖细胞：一种能够产生致力于导管形成的子细胞，另一种只能产生致力于小叶功能的子细胞。(C)出版社：Academic Press
An important feature of the mammary gland is the regenerative capacity of its epithelium which is demonstrated upon successive cycles of lactation and involution. Pregnant mice expressing a whey-acidic protein (WAP) promoter-driven transforming growth factor-beta 1 (TGF beta 1) cDNA are unable either to generate a secretory mammary epithelium or to lactate. Here we investigate whether ectopic TGF beta 1 induces this phenotype by affecting the transgenic epithelium directly or in trans. Reciprocal transplantation of mammary tissue between normal and transgenic hosts resulted in the development of the respective phenotypes of the transplants within the same mammary fat pad. When isolated mammary epithelial cells from both were mixed before implantation so that transgenic and normal epithelium would develop together more proximately, both phenotypes were simultaneously observed in the resultant chimeric mammary outgrowths. Since no trans effect was detectable, we hypothesize that early expression of the transgene results in compromised lobular progenitor cells through an intracrine mechanism. Consistent with this posit, WAP promoter-driven protein expression was detected in individual cells of the subtending ducts of immature females at estrus. Transplantation of WAP-TGF beta 1 mammary gland into nonpregnant hosts revealed that transgenic implants, even those from young postpubertal virgin females, had a diminished ability to repopulate epithelium-free mammary fat pads. Accordingly, the ectopic expression of WAP-TGF beta 1 not only impairs lobular progenitors, but also promotes an early senescence of the regenerative capacity of the mammary ductal epithelium. This leads us to propose that mammary epithelial stem cells give rise to two functionally distinct progenitor cells in the mammary gland epithelium: one capable of producing daughters committed to ductal formation, the other capable only of producing daughters committed to lobular function. (C) 1995 Academic Press, Inc.