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Regulation of mesenchymal stem cell differentiation and mesenchymal cell fate.

机译：调节间充质干细胞的分化和间充质细胞的命运。

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摘要

Bone marrow derived mesenchymal stem cells (MSC) are multipotent, self-renewing, mesodermal-origin stem cells sequestered in the endosteal compartment. MSC are maintained in a relative state of quiescence in vivo but in response to a variety of physiological and pathological stimuli, proliferate and differentiate into osteoblasts, chondrocytes, adipocytes, or hematopoiesis-supporting stromal cells. Little is understood regarding the cellular or molecular events underlying MSC fate decisions. We evaluated gene expression of early passage hMSC cultured under serum free conditions.; In the absence of osteoinductive stimuli, these cells express low to moderate levels of the bone specific or bone associated transcription factors Runx-2 and Dlx-5, as well as the bone associated extracellular matrix proteins, osteopontin and osteocalcin. Expression of BMP-6, but not BMP-2, 4, and 7 was detected in hMSC. Expression of several Wnt family members was detected in hMSC, including the canonical Wnts, Wnt-4b, 5b, 7a, 8b, and 10b, and the non-canonical Wnt11. We also examined the osteogenic potential of hMSC in response to growth factors and found that human MSC (hMSC) cultured in defined, serum-free conditions respond to BMPs with osteogenic commitment, differentiation, and hydroxyapatite deposition. Addition of BMP-6 to hMSC induces the expression or up-regulation of a repertoire of osteoblast-related genes including type I collagen, osteocalcin, bone sialoprotein, and their regulatory transcription factors Cbfa1/Runx-2, and Osterix. This translates into increased production of osteogenic extracellular matrix (ECM) with subsequent hydroxyapatite deposition.; Osterix, a BMP induced osteoblast transcription factor expressed at the earliest stages of differentiation, appears to regulate expression of bone sialoprotein and osteomodulin, bone extracellular matrix proteins essential for the earliest stages of bone formation. At the latest stages of BMP induced hMSC osteoblast differentiation, we observed activation of Notch signaling, indicating that Notch may be required for terminal differentiation of hMSC and osteoblast function.; Wnt11, an endogenous factor expressed at moderate levels in murine pre-osteoblasts, enhances BMP osteoinduction of these cells. Murine calvarial pre-osteoblasts overexpressing Wnt11 have elevated levels of cytosolic and nuclear beta-cateninin, hallmarks of canonical Wnt signaling. These cells demonstrate increased osteoblast differentiation and function at a molecular and phenotypic level. These studies identify Wnt11 as a novel osteogenic factor.
机译：骨髓来源的间充质干细胞（MSC）是多能的，自我更新的，起源于中胚层的干细胞，被隔离在骨膜内腔中。 MSC在体内保持相对静止状态，但是响应于各种生理和病理刺激，增殖并分化为成骨细胞，软骨细胞，脂肪细胞或支持造血的基质细胞。关于MSC命运决定的细胞或分子事件知之甚少。我们评估了在无血清条件下培养的早期传代hMSC的基因表达。在没有骨诱导性刺激的情况下，这些细胞表达低至中等水平的骨特异性或与骨相关的转录因子Runx-2和Dlx-5，以及与骨相关的细胞外基质蛋白，骨桥蛋白和骨钙蛋白。在hMSC中检测到BMP-6的表达，但未检测到BMP-2、4和7的表达。在hMSC中检测到多个Wnt家族成员的表达，包括经典Wnts，Wnt-4b，5b，7a，8b和10b，以及非经典Wnt11。我们还检查了hMSC对生长因子的响应的成骨潜能，发现在定义的无血清条件下培养的人MSC（hMSC）对BMP具有成骨作用，分化和羟基磷灰石沉积的反应。在hMSC中添加BMP-6可诱导成骨细胞相关基因（包括I型胶原，骨钙素，骨唾液蛋白及其调节转录因子Cbfa1 / Runx-2和Osterix）的表达或上调。转化为成骨细胞外基质（ECM）的产量增加，随后羟基磷灰石沉积。 Osterix是BMP诱导的成骨细胞转录因子，在分化的最早阶段表达，它似乎在调节骨唾液蛋白和骨调节蛋白的表达，骨唾液酸蛋白和骨调节蛋白是在骨形成的最早阶段必不可少的骨细胞外基质蛋白。在BMP诱导hMSC成骨细胞分化的最新阶段，我们观察到了Notch信号的激活，表明Notch可能是hMSC终末分化和成骨细胞功能所必需的。 Wnt11是在鼠成骨细胞中以中等水平表达的内源性因子，可增强这些细胞的BMP骨诱导作用。过量表达Wnt11的鼠颅盖成骨细胞具有升高的胞质和核β-cateninin水平，这是典型Wnt信号的标志。这些细胞在分子和表型水平上显示出增加的成骨细胞分化和功能。这些研究将Wnt11鉴定为一种新型成骨因子。

著录项

  • 作者

    Friedman, Michael Steven.;

  • 作者单位

    University of Michigan.;

  • 授予单位 University of Michigan.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2006
  • 页码 147 p.
  • 总页数 147
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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