Donor cell-derived osteopoiesis originates from a self-renewing stem cell with a limited regenerative contribution after transplantation
Donor cell-derived osteopoiesis originates from a self-renewing stem cell with a limited regenerative contribution after transplantation
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DOI：
10.1182/blood-2007-10-115725
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发表时间：
2008-04-15
期刊：
影响因子：
20.3
通讯作者：
Horwitz, Edwin M.
中科院分区：
文献类型：
--
作者：
Dominici, Massimo;Marino, Roberta;Horwitz, Edwin M.
原则上，骨髓移植应能有效治疗间充质干细胞缺陷引起的疾病。骨病成骨不全的结果支持这一假设，尽管移植后早期的临床改善率并没有长期持续，这对供体来源的间充质祖细胞的再生能力提出了疑问。因此，我们研究了表达gfp的非粘附骨髓细胞移植小鼠后的成骨植入动力学和组织学/解剖模式。在52周内对供体来源的GFP（+）细胞的连续跟踪显示，在骨骺和干骺中有大量的供体来源的成骨细胞/骨细胞簇，但在骨干中没有，这种分布与最初的造血植入部位相似。移植后24周，成骨嵌合率从大约30%下降到10%，此后下降到可以忽略不计的水平。二次移植研究为骨髓移植中自我更新的成骨干细胞提供了证据。我们得出的结论是，可移植的、原始的、自我更新的成骨细胞在非贴壁骨髓细胞群中植入内皮生态位，像造血干细胞一样，再生了所有骨细胞的很大一部分。缺乏持久的供体来源的成骨可能反映了内在的遗传程序或外源性环境信号抑制供体干细胞的分化能力。
In principle, bone marrow transplantation should offer effective treatment for disorders originating from defects in mesenchymal stem cells. Results with the bone disease osteogenesis imperfecta support this hypothesis, although the rate of clinical improvement seen early after transplantation does not persist long term, raising questions as to the regenerative capacity of the donor-derived mesenchymal progenitors. We therefore studied the kinetics and histologic/anatomic pattern of osteopoietic engraftment after transplantation of GFP-expressing nonadherent marrow cells in mice. Serial tracking of donor-derived GFP(+) cells over 52 weeks showed abundant clusters of donor-derived osteoblasts/osteocytes in the epiphysis and metaphysis but not the diaphysis, a distribution that paralleled the sites of initial hematopoietic engraftment. Osteopoietic chimerism decreased from approximately 30% to 10% by 24 weeks after transplantation, declining to negligible levels thereafter. Secondary transplantation studies provided evidence for a self-renewing osteopoietic stem cell in the marrow graft. We conclude that a transplantable, primitive, self-renewing osteopoietic cell within the nonadherent marrow cell population engrafts in an endosteal niche, like hematopoietic stem cells, and regenerates a significant fraction of all bone cells. The lack of durable donor-derived osteopoiesis may reflect an intrinsic genetic program or exogenous environmental signaling that suppresses the differentiation capacity of the donor stem cells.