Extracellular matrix control mesenchymal stem cell fate

骨髓间充质干细胞(MSCs)复制以产生相同的子代干细胞和 可分化为多种不同类型的细胞，包括成骨细胞。然而，MSCs失去了其独特的 在组织培养塑料上培养时的特性。这表明骨髓的一个关键特征 在这样的培养系统中，缺乏有助于保留干细胞特性的微环境-a 这种情况损害了对骨髓间充质干细胞的研究，限制了它们的治疗潜力。在其他组织中， 细胞外基质(ECM)在控制干细胞行为方面发挥着重要作用。 暴露于增长因素。我们还知道，ECM的一个蛋白多糖成分，Biglycan，扮演着一个 在维护MSC数量和功能方面发挥重要作用。初步研究表明， 在由小鼠骨髓基质细胞制成的无细胞ECM上，MSCs保留了它们的干细胞特性， 包括自我更新的能力，保持无差别状态，以及对 外源性BMP-2促成骨作用的实验研究这一发现可以用ECM的证据解释 隔离基质细胞分泌的内源性BMP-2。上述观察结果构成了 假设由骨髓基质细胞产生的细胞外基质特异性地支配骨髓间充质干细胞对 自我更新和分化为特定的谱系，至少部分是通过调节细胞对因子的暴露 它们控制着它们的复制和分化。建议进行实验以确定主要的胶原蛋白， 小鼠骨髓基质细胞来源的ECM黏附蛋白和蛋白多糖成分的研究 免疫染色和共聚焦显微镜；并确定基质细胞来源的细胞外基质是否独特 其保存MSC属性的能力。此外，促成骨因子的数量，包括 将测定基质细胞来源的ECM中的IGF-I、TGF-(3)、PDGF、VEGF和BMP-2； 这些生长因子在本ECM中的水平将被调查。最后， 在这种ECM上生长的MSCs是否保持其干细胞特性的问题将在以下体内进行测试 移植到免疫缺陷小鼠体内。这些研究将为调查年龄是否- 相关的骨丢失部分是由于骨的ECM改变引起的MSC的异常行为。 骨髓。

Mesenchymal stem cells (MSCs) of the bone marrow replicate to produce identical daughter stem cells and can differentiate into many different cell types inculding osteoblasts. However, MSCs lose their unique properties when cultured on tissue culture plastic. This indicates that a critical feature of the marrow microenvironment that facilitates retention of stem cell properties is missing in such culture systems - a situation that impairs the study of MSCs and limits their therapeutic potential. In other tissues, the extracellular matrix (ECM) plays an important role in controlling stem cell behavior by governing their exposure to growth factors. It is also known that a proteoglycan component of the ECM, biglycan, plays an important role in the maintenance of MSC number and function. Preliminary studies indicated that culture of MSCs on a cell-free ECM made by murine marrow-derived stromal cells preserved their stem cell properties, including the capacity to self-renew, the maintenance of an undifferentiated state, and responsiveness to the pro-osteoblastogenic effect of exogenous BMP-2. This finding may be explained by evidence that the ECM sequestered endogenous BMP-2 secreted by the stromal cells. The above observations form the basis of the hypothesis that the ECM made by marrow stromal cells specifically governs the ability of MSCs to both self-renew and differentiate into a particular lineage, at least in part, by regulating exposure of cells to factors that control their replication and differentiation. Experiments are proposed to identify the principal collagen, adhesion protein and proteoglycan components of murine marrow stromal cell-derived ECM using immunostaining and confocal microscopy; and to determine whether the stromal cell-derived ECM is unique in its ability to preserve MSC properties. In addition, the amount of pro-osteoblastogenic factors, including IGF-I, TGF-(3, PDGF, VEGF, and BMP-2, in the stromal cell-derived ECM will be determined; and the impact of biglycan deficiency on the level of these growth factors in this ECM will be investigated. Finally, the question of whether MSCs grown on this ECM retain their stem cell properties will be tested in vivo following transplantation into immunodeficient mice. These studies will set the stage for investigating whether age- related bone loss is due in part to aberrant MSC behavior caused by alteration in the ECM of the bone marrow.