Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Nat Med. 2010 Dec;16(12):1400-6. doi: 10.1038/nm.2252. Epub 2010 Nov 21.
Mesenchymal stem cells can give rise to several cell types, but varying results depending on isolation methods and tissue source have led to controversies about their usefulness in clinical medicine. Here we show that vascular endothelial cells can transform into multipotent stem-like cells by an activin-like kinase-2 (ALK2) receptor-dependent mechanism. In lesions from individuals with fibrodysplasia ossificans progressiva (FOP), a disease in which heterotopic ossification occurs as a result of activating ALK2 mutations, or from transgenic mice expressing constitutively active ALK2, chondrocytes and osteoblasts expressed endothelial markers. Lineage tracing of heterotopic ossification in mice using a Tie2-Cre construct also suggested an endothelial origin of these cell types. Expression of constitutively active ALK2 in endothelial cells caused endothelial-to-mesenchymal transition and acquisition of a stem cell-like phenotype. Similar results were obtained by treatment of untransfected endothelial cells with the ligands transforming growth factor-β2 (TGF-β2) or bone morphogenetic protein-4 (BMP4) in an ALK2-dependent manner. These stem-like cells could be triggered to differentiate into osteoblasts, chondrocytes or adipocytes. We suggest that conversion of endothelial cells to stem-like cells may provide a new approach to tissue engineering.
间充质干细胞可以分化为多种细胞类型，但由于分离方法和组织来源的不同，导致其在临床医学中的应用存在争议。在这里，我们证明血管内皮细胞可以通过激活素样激酶 2 (ALK2) 受体依赖性机制转化为多能干细胞样细胞。在纤维发育不良性骨化进展（FOP）患者的病变组织中，由于激活的 ALK2 突变导致异位骨化，或者在表达组成性激活的 ALK2 的转基因小鼠中，软骨细胞和成骨细胞表达内皮标记物。使用 Tie2-Cre 构建体对小鼠异位骨化的谱系追踪也表明这些细胞类型来源于内皮细胞。内皮细胞中组成性激活的 ALK2 导致内皮细胞向间充质转化并获得干细胞样表型。未转染的内皮细胞用转化生长因子-β2（TGF-β2）或骨形态发生蛋白-4（BMP4）以 ALK2 依赖的方式处理也得到了类似的结果。这些干细胞样细胞可以被诱导分化为成骨细胞、软骨细胞或脂肪细胞。我们认为，内皮细胞向干细胞样细胞的转化可能为组织工程提供一种新方法。
