Cancer Cell Biology Program, School of Medicine, West Virginia University, Morgantown, West Virginia, United States of America.
PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
Hematopoietic reconstitution, following bone marrow or stem cell transplantation, requires a microenvironment niche capable of supporting both immature progenitors and stem cells with the capacity to differentiate and expand. Osteoblasts comprise one important component of this niche. We determined that treatment of human primary osteoblasts (HOB) with melphalan or VP-16 resulted in increased phospho-Smad2, consistent with increased TGF-β1 activity. This increase was coincident with reduced HOB capacity to support immature B lineage cell chemotaxis and adherence. The supportive deficit was not limited to committed progenitor cells, as human embryonic stem cells (hESC) or human CD34+ bone marrow cells co-cultured with HOB pre-exposed to melphalan, VP-16 or rTGF-β1 had profiles distinct from the same populations co-cultured with untreated HOB. Functional support deficits were downstream of changes in HOB gene expression profiles following chemotherapy exposure. Melphalan and VP-16 induced damage of HOB suggests vulnerability of this critical niche to therapeutic agents frequently utilized in pre-transplant regimens and suggests that dose escalated chemotherapy may contribute to post-transplantation hematopoietic deficits by damaging structural components of this supportive niche.
骨髓或干细胞移植后造血重建需要一个能够支持未成熟祖细胞和具有分化和扩增能力的干细胞的微环境龛。成骨细胞是该龛位的一个重要组成部分。我们发现，用美法仑或 VP-16 处理人原代成骨细胞（HOB）会导致磷酸化 Smad2 增加，这与 TGF-β1 活性增加一致。这种增加与 HOB 支持未成熟 B 谱系细胞趋化性和黏附的能力降低有关。这种支持不足不仅限于定向祖细胞，因为与未经处理的 HOB 共培养的人胚胎干细胞（hESC）或人 CD34+骨髓细胞与预先暴露于美法仑、VP-16 或 rTGF-β1 的 HOB 共培养时，其特征与与未经处理的 HOB 共培养的相同群体明显不同。化疗暴露后 HOB 基因表达谱的变化是功能支持不足的下游事件。美法仑和 VP-16 诱导 HOB 损伤表明，这种关键龛位容易受到移植前方案中常用的治疗药物的影响，并表明剂量递增化疗可能通过破坏支持该龛位的结构成分导致移植后造血不足。
