Abbasizadeh Nastaran, Burns Christian S, Verrinder Ruth, Ghazali Farhad, Seyedhassantehrani Negar, Spencer Joel A
Department of Bioengineering, University of California, Merced, Merced, CA, United States.
Center for Cellular and Biomolecular Machines, University of California, Merced, Merced, CA, United States.
Front Cell Dev Biol. 2024 Jul 30;12:1441381. doi: 10.3389/fcell.2024.1441381. eCollection 2024.
Preparative regimens before Hematopoietic Cell Transplantation (HCT) damage the bone marrow (BM) microenvironment, potentially leading to secondary morbidity and even mortality. The precise effects of cytotoxic preconditioning on bone and BM remodeling, regeneration, and subsequent hematopoietic recovery over time remain unclear. Moreover, the influence of recipient age and cytotoxic dose have not been fully described. In this study, we longitudinally investigated bone and BM remodeling after busulfan treatment with low intensity (LI) and high intensity (HI) regimens as a function of animal age. As expected, higher donor chimerism was observed in young mice in both LI and HI regimens compared to adult mice. Noticeably in adult mice, significant engraftment was only observed in the HI group. The integrity of the blood-bone marrow barrier in calvarial BM blood vessels was lost after busulfan treatment in the young mice and remained altered even 6 weeks after HCT. In adult mice, the severity of vascular leakage appeared to be dose-dependent, being more pronounced in HI compared to LI recipients. Interestingly, no noticeable change in blood flow velocity was observed following busulfan treatment. imaging of the long bones revealed a reduction in the frequency and an increase in the diameter and density of the blood vessels shortly after treatment, a phenomenon that largely recovered in young mice but persisted in older mice after 6 weeks. Furthermore, analysis of bone remodeling indicated a significant alteration in bone turnover at 6 weeks compared to earlier timepoints in both young and adult mice. Overall, our results reveal new aspects of bone and BM remodeling, as well as hematopoietic recovery, which is dependent on the cytotoxic dose and recipient age.
造血细胞移植（HCT）前的预处理方案会损害骨髓（BM）微环境，可能导致继发性发病甚至死亡。细胞毒性预处理对骨骼和骨髓重塑、再生以及随后随时间的造血恢复的确切影响仍不清楚。此外，受者年龄和细胞毒性剂量的影响尚未得到充分描述。在本研究中，我们纵向研究了白消安低强度（LI）和高强度（HI）方案治疗后骨骼和骨髓重塑随动物年龄的变化。正如预期的那样，与成年小鼠相比，LI和HI方案的年轻小鼠中观察到更高的供体嵌合率。值得注意的是，在成年小鼠中，仅在HI组中观察到显著的植入。年轻小鼠白消安治疗后颅骨骨髓血管中的血骨髓屏障完整性丧失，甚至在HCT后6周仍保持改变。在成年小鼠中，血管渗漏的严重程度似乎呈剂量依赖性，与LI受体相比，HI受体中更明显。有趣的是，白消安治疗后未观察到血流速度有明显变化。长骨成像显示治疗后不久血管频率降低，直径和密度增加，这种现象在年轻小鼠中大多恢复，但在老年小鼠中6周后仍持续存在。此外，骨重塑分析表明，与年轻和成年小鼠的早期时间点相比，6周时骨转换有显著改变。总体而言，我们的结果揭示了骨骼和骨髓重塑以及造血恢复的新方面，这取决于细胞毒性剂量和受者年龄。
