Laboratory of Ageing Biology and Stem Cells, European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, 9713 AV Groningen, Netherlands.
J Exp Med. 2014 Mar 10;211(3):487-97. doi: 10.1084/jem.20131804. Epub 2014 Feb 24.
Hematopoietic stem cells (HSCs) are able to migrate through the blood stream and engraft bone marrow (BM) niches. These features are key factors for successful stem cell transplantations that are used in cancer patients and in gene therapy protocols. It is unknown to what extent transplanted HSCs distribute throughout different anatomical niches in the BM and whether this changes with age. Here we determine the degree of hematopoietic migration at a clonal level by transplanting individual young and aged mouse HSCs labeled with barcoded viral vector, followed by assessing the skeletal distribution of hundreds of HSC clones. We detected highly skewed representation of individual clones in different bones at least 11 mo after transplantation. Importantly, a single challenge with the clinically relevant mobilizing agent granulocyte colony-stimulating factor (G-CSF) caused rapid redistribution of HSCs across the skeletal compartments. Old and young HSC clones showed a similar level of migratory behavior. Clonal make-up of blood of secondary recipients recapitulates the barcode composition of HSCs in the bone of origin. These data demonstrate a previously unanticipated high skeletal disequilibrium of the clonal composition of HSC pool long-term after transplantation. Our findings have important implications for experimental and clinical and stem cell transplantation protocols.
造血干细胞 (HSCs) 能够通过血液迁移并植入骨髓 (BM) 龛位。这些特征是成功进行癌症患者和基因治疗方案中使用的干细胞移植的关键因素。目前尚不清楚移植的 HSCs 在多大程度上分布在 BM 中的不同解剖龛位，以及这种分布是否会随年龄而变化。在这里，我们通过移植用带有条码病毒载体标记的个体年轻和年老的小鼠 HSCs，在克隆水平上确定造血迁移的程度，然后评估数百个 HSC 克隆在骨骼中的分布。我们发现，在移植后至少 11 个月，个体克隆在不同骨骼中的代表性存在严重的偏倚。重要的是，单次临床相关动员剂粒细胞集落刺激因子 (G-CSF) 的刺激会导致 HSCs 在骨骼隔室中快速重新分布。年老和年轻的 HSC 克隆表现出相似的迁移行为。二级受者血液中的克隆组成再现了 HSCs 在起源骨骼中的条码组成。这些数据表明，在移植后很长一段时间内，HSC 池的克隆组成在骨骼中存在以前未预料到的高度失衡。我们的发现对实验和临床以及干细胞移植方案具有重要意义。
