Dominici Massimo, Marino Roberta, Rasini Valeria, Spano Carlotta, Paolucci Paolo, Conte Pierfranco, Hofmann Ted J, Horwitz Edwin M
Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy.
Blood. 2008 Apr 15;111(8):4386-91. doi: 10.1182/blood-2007-10-115725. Epub 2008 Jan 8.
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.
原则上，骨髓移植应为源自间充质干细胞缺陷的疾病提供有效的治疗方法。骨病成骨不全症的治疗结果支持了这一假说，尽管移植后早期出现的临床改善率并未长期持续，这引发了关于供体来源的间充质祖细胞再生能力的疑问。因此，我们研究了在小鼠中移植表达绿色荧光蛋白（GFP）的非贴壁骨髓细胞后骨生成植入的动力学以及组织学/解剖学模式。对供体来源的GFP（+）细胞进行52周的连续追踪显示，在骨骺和干骺端而非骨干中有大量供体来源的成骨细胞/骨细胞簇，这种分布与初始造血植入的部位平行。移植后24周，骨生成嵌合体从约30%降至10%，此后降至可忽略不计的水平。二次移植研究为骨髓移植物中存在自我更新的骨生成干细胞提供了证据。我们得出结论，非贴壁骨髓细胞群体中存在一种可移植的、原始的、自我更新的骨生成细胞，它像造血干细胞一样植入骨内膜龛，并再生大部分骨细胞。缺乏持久的供体来源骨生成可能反映了一种抑制供体干细胞分化能力的内在遗传程序或外源性环境信号。
