Universitätsklinik und Poliklinik für Innere Medizin IV, Universitätsklinikum Halle, Halle (Saale), Germany.
Klinik für Innere Medizin V, Universitätsklinikum Heidelberg, Heidelberg, Germany.
Blood Adv. 2023 Jun 27;7(12):2811-2824. doi: 10.1182/bloodadvances.2022008510.
Engraftment and differentiation of donor hematopoietic stem cells is decisive for the clinical success of allogeneic stem cell transplantation (alloSCT) and depends on the recipient's bone marrow (BM) niche. A damaged niche contributes to poor graft function after alloSCT; however, the underlying mechanisms and the role of BM multipotent mesenchymal stromal cells (MSC) are ill-defined. Upon multivariate analysis in 732 individuals, we observed a reduced presence of proliferation-capable MSC in BM aspirates from patients (N = 196) who had undergone alloSCT. This was confirmed by paired analysis in 30 patients showing a higher frequency of samples with a lack of MSC presence post-alloSCT compared with pre-alloSCT. This reduced MSC presence was associated with reduced survival of patients after alloSCT and specifically with impaired graft function. Post-alloSCT MSC showed diminished in vitro proliferation along with a transcriptional antiproliferative signature, upregulation of epithelial-mesenchymal transition and extracellular matrix pathways, and altered impact on cytokine release upon contact with hematopoietic cells. To avoid in vitro culture bias, we isolated the CD146+/CD45-/HLA-DR- BM cell fraction, which comprised the entire MSC population. The post-alloSCT isolated native CD146+MSC showed a similar reduction in proliferation capacity and shared the same antiproliferative transcriptomic signature as for post-alloSCT colony-forming unit fibroblast-derived MSC. Taken together, our data show that alloSCT confers damage to the proliferative capacity of native MSC, which is associated with reduced patient survival after alloSCT and impaired engraftment of allogeneic hematopoiesis. These data represent the basis to elucidate mechanisms of BM niche reconstitution after alloSCT and its therapeutic manipulation.
供体造血干细胞的植入和分化对异基因干细胞移植（alloSCT）的临床成功至关重要，并且依赖于受者的骨髓（BM）龛位。受损的龛位会导致 alloSCT 后移植物功能不良；然而，其潜在机制和 BM 多能间充质基质细胞（MSC）的作用仍未明确。在对 732 个人进行多变量分析后，我们观察到接受 alloSCT 的患者（N=196）的 BM 抽吸物中增殖能力的 MSC 存在减少。在 30 名患者的配对分析中得到了证实，与 alloSCT 前相比，alloSCT 后缺乏 MSC 存在的样本频率更高。这种 MSC 存在减少与 alloSCT 后患者的生存率降低相关，并且与移植物功能受损具体相关。alloSCT 后 MSC 的体外增殖能力降低，同时具有转录性抗增殖特征，上皮-间充质转化和细胞外基质途径的上调，以及与造血细胞接触时对细胞因子释放的改变影响。为避免体外培养偏差，我们分离了 CD146+/CD45-/HLA-DR- BM 细胞群，该细胞群包含了整个 MSC 群体。分离自 alloSCT 的天然 CD146+MSC 显示出相似的增殖能力降低，并具有与 alloSCT 集落形成单位成纤维细胞衍生的 MSC 相同的抗增殖转录组特征。总之，我们的数据表明 alloSCT 对天然 MSC 的增殖能力造成损害，这与 alloSCT 后患者生存率降低和异基因造血植入受损相关。这些数据代表阐明 alloSCT 后 BM 龛位重建及其治疗干预的机制的基础。
