George Andrea L, Boulanger Corinne A, Smith Gilbert H
Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Aging (Albany NY). 2016 Jul;8(7):1353-63. doi: 10.18632/aging.100985.
It has been proposed that the erosion of telomere length is a limiting factor in replicative capacity and important in cell senescence. To determine if this activity was essential in the mouse mammary gland in vivo, we serially transplanted mammary fragments from wild type (TER+/+), heterozygous (TER+/-), and homozygous (TER-/-) mammary tissues into the cleared mammary fat pads of immune-compromised nude mice. Individual implants from both homozygous and heterozygous TER null outgrowths showed growth senescence beginning at transplant generation two, earlier than implants from TER+/+ mammary glands which continued to show growth. This result suggests that either mammary epithelial stem cells maintain their telomere length in order to self renew, or that the absence or reduction of telomerase template results in more frequent death/extinction of stem cells during symmetric divisions. A third possibility is the inability of signaling cells in the niche to replicate resulting in reduction of the maintenance signals necessary for stem cell renewal. Consistent with this, examination of senescent outgrowths revealed the absence of estrogen receptor alpha (ERα+) epithelium although progesterone receptor (PR+) cells were abundant. Despite their inability to establish mammary growth in vivo, TER+/- cells were able to direct neural stem cells to mammary cell fates.
有人提出，端粒长度的缩短是复制能力的限制因素，并且在细胞衰老中起重要作用。为了确定这种活性在体内小鼠乳腺中是否必不可少，我们将野生型（TER+/+）、杂合型（TER+/-）和纯合型（TER-/-）乳腺组织的乳腺片段连续移植到免疫缺陷裸鼠的清除乳腺脂肪垫中。来自纯合型和杂合型TER缺失生长物的单个植入物在移植第二代开始显示出生长衰老，早于来自TER+/+乳腺的植入物，后者继续显示出生长。这一结果表明，要么乳腺上皮干细胞维持其端粒长度以实现自我更新，要么端粒酶模板的缺失或减少导致干细胞在对称分裂期间更频繁地死亡/灭绝。第三种可能性是生态位中的信号细胞无法复制，导致干细胞更新所需的维持信号减少。与此一致的是，对衰老生长物的检查显示，尽管孕激素受体（PR+）细胞丰富，但缺乏雌激素受体α（ERα+）上皮。尽管TER+/-细胞无法在体内建立乳腺生长，但它们能够将神经干细胞引导至乳腺细胞命运。
