Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel, 76100.
Stem Cell Rev Rep. 2014 Jun;10(3):376-88. doi: 10.1007/s12015-014-9498-z.
The outstanding heterogeneity of stem cell populations is a major obstacle on the way to their clinical application. It is therefore paramount to identify the molecular mechanisms that underlay this heterogeneity. Individually derived bone marrow mesenchymal stromal cells (MSCs) preparations, studied here, diverged markedly in various properties, despite of being all tripotent in their differentiation potential. Microarray analysis showed that MSC diversity is evident also in highly variable gene expression patterns. Differentially expressed genes were significantly enriched in toll-like receptors (TLRs) and differentiation pathways. Marked differences were observed in LPS binding protein (LBP) and transforming growth factor (TGF)β1 expression. These differences correlated with MSC functionality. Therefore, the possible contribution of these molecules to MSC diversity was examined. In the TLR signaling pathway, LBP levels predicted the ability of specific MSCs to secrete interleukin (IL)-6 in response to LPS. A relatively higher expression of TGFβ1 endowed MSCs with a capacity to respond to IL-1β by reduced osteogenic differentiation. This study thus demonstrates major diversity within MSC isolates, which appears early on following derivation and persists following long-term culture. MSC heterogeneity results from highly variable transcriptome. Differential expression of LBP and TGFβ1, along with other genes, in different MSC preparations, produces the variable responses to external stimuli.
干细胞群体的显著异质性是其临床应用的主要障碍。因此，确定这种异质性的分子机制至关重要。本研究中，个体分离的骨髓间充质基质细胞（MSC）制剂在各种特性上存在明显差异，尽管它们在分化潜能方面均具有三向分化潜能。微阵列分析表明，MSC 的多样性也表现在高度可变的基因表达模式中。差异表达的基因在 Toll 样受体（TLR）和分化途径中显著富集。LPS 结合蛋白（LBP）和转化生长因子（TGF）β1 的表达存在明显差异。这些差异与 MSC 的功能相关。因此，研究了这些分子对 MSC 多样性的可能贡献。在 TLR 信号通路中，LBP 水平预测了特定 MSC 分泌白细胞介素（IL）-6 以响应 LPS 的能力。TGFβ1 的相对较高表达使 MSC 能够通过减少成骨分化来响应 IL-1β。因此，这项研究表明 MSC 分离物存在显著的异质性，这种异质性在分离后早期就出现，并在长期培养后仍然存在。MSC 异质性源于高度可变的转录组。不同 MSC 制剂中 LBP 和 TGFβ1 以及其他基因的差异表达导致对外部刺激的可变反应。
