Stem Cell Biology Department, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India.
Experimental Animal Facility, ICMR-National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India.
Stem Cell Rev Rep. 2020 Oct;16(5):909-921. doi: 10.1007/s12015-020-09998-1.
Lifelong homeostasis of bone marrow is maintained by the resident stem cells that include the quiescent very small embryonic-like stem cells (VSELs) and lineage restricted, tissue committed 'progenitors' hematopoietic stem cells (HSCs). Niche providing mesenchymal stromal cells (MSCs) regulate the function of VSELs/HSCs by providing crucial paracrine support. Any dysfunction of stem cells and/or their niche leads to disease state. The stem cells biology gets affected with age leading to a myeloid bias in differentiation of HSCs and increased incidence of myeloid leukemia. Present study was undertaken to enumerate VSELs, HSCs and MSCs and evaluate their response on D4 and D10 after chemotherapy with 5-Fluorouracil (5-FU) in young and aged mouse bone marrow. Stem cells were activated in response to 5-FU induced stress in an attempt to restore homeostasis. Although absolute numbers of VSELs and HSCs did not differ much between young and aged mice, their tendency to proliferate was higher on D4 in aged mice. However, ability to revert back to basal numbers and their differentiation was affected on D10 in aged marrow. Stem cells from aged bone marrow showed greater ability to form CFUs on D10 after 5-FU treatment. CD44 positive aged MSCs also showed increased proliferation on D10. Transplanting MSCs from young mice in 5-FU treated aged marrow helped improve hematopoiesis. The results suggest that no significant intrinsic changes occur as proliferative ability of stem cells remains unaffected but the niche gets affected with age leading to excessive self-renewal and compromised differentiation. This may explain increased incidence of leukemia with age.
骨髓的终身稳态由驻留的干细胞维持，包括静止的非常小的胚胎样干细胞（VSELs）和谱系受限的组织定向“祖细胞”造血干细胞（HSCs）。提供龛位的间充质基质细胞（MSCs）通过提供关键的旁分泌支持来调节 VSELs/HSCs 的功能。干细胞及其龛位的任何功能障碍都会导致疾病状态。随着年龄的增长，干细胞生物学受到影响，导致 HSCs 的分化向髓样偏倚，并增加髓性白血病的发病率。本研究旨在计数年轻和老年小鼠骨髓中经 5-氟尿嘧啶（5-FU）化疗后第 4 天和第 10 天的 VSELs、HSCs 和 MSCs，并评估它们的反应。干细胞在试图恢复稳态时会对 5-FU 诱导的应激做出反应而被激活。尽管年轻和老年小鼠之间的 VSELs 和 HSCs 的绝对数量没有太大差异，但老年小鼠在第 4 天的增殖趋势更高。然而，在第 10 天，它们恢复到基础数量和分化的能力受到影响。来自老年骨髓的干细胞在 5-FU 处理后第 10 天形成 CFUs 的能力更强。CD44 阳性的老年 MSC 也显示出在第 10 天增殖增加。在 5-FU 处理的老年骨髓中移植来自年轻小鼠的 MSC 有助于改善造血。结果表明，没有发生明显的固有变化，因为干细胞的增殖能力不受影响，但龛位随着年龄的增长而受到影响，导致过度自我更新和分化受损。这可以解释为什么随着年龄的增长白血病的发病率会增加。
