School of Biomedical Science, Institute of Tissue Engineering and Regenerative Medicine, And Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; Tissue Engineering Laboratory, Department of Mechanical Engineering, The University of Hong Kong, Pok Fu Lam Road, Hong Kong SAR, China; Advanced Biomedical Instrumentation Centre, Hong Kong Science Park, Shatin, New Territories, Hong Kong SAR, China.
School of Biomedical Science, Institute of Tissue Engineering and Regenerative Medicine, And Department of Biomedical Engineering, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China; Tissue Engineering Laboratory, Department of Mechanical Engineering, The University of Hong Kong, Pok Fu Lam Road, Hong Kong SAR, China.
Biomaterials. 2025 Jan;312:122719. doi: 10.1016/j.biomaterials.2024.122719. Epub 2024 Jul 27.
Acute myeloid leukemia (AML) is a deadly form of leukemia with ineffective traditional treatment and frequent chemoresistance-associated relapse. Personalized drug screening holds promise in identifying optimal regimen, nevertheless, primary AML cells undergo spontaneous apoptosis during cultures, invalidating the drug screening results. Here, we reconstitute a 3D osteogenic niche (3DON) mimicking that in bone marrow to support primary AML cell survival and phenotype maintenance in cultures. Specifically, 3DON derived from osteogenically differentiated mesenchymal stem cells (MSC) from healthy and AML donors are co-cultured with primary AML cells. The AML cells under the AML_3DON niche showed enhanced viability, reduced apoptosis and maintained CD33 CD34phenotype, associating with elevated secretion of anti-apoptotic cytokines in the AML_3DON niche. Moreover, AML cells under the AML_3DON niche exhibited low sensitivity to two FDA-approved chemotherapeutic drugs, further suggesting the physiological resemblance of the AML_3DON niche. Most interestingly, AML cells co-cultured with the healthy_3DON niche are highly sensitive to the same sample drugs. This study demonstrates the differential responses of AML cells towards leukemic and healthy bone marrow niches, suggesting the impact of native cancer cell niche in drug screening, and the potential of re-engineering healthy bone marrow niche in AML patients as chemotherapeutic adjuvants overcoming chemoresistance, respectively.
急性髓细胞白血病（AML）是一种致命的白血病形式，传统治疗效果不佳，且经常发生与化疗耐药相关的复发。个性化药物筛选有望确定最佳方案，但原代 AML 细胞在培养过程中会自发凋亡，从而使药物筛选结果无效。在这里，我们重建了一个 3D 成骨龛（3DON），模拟骨髓中的情况，以支持原代 AML 细胞在培养中的存活和表型维持。具体来说，来自健康和 AML 供体的成骨分化间充质干细胞（MSC）的 3DON 与原代 AML 细胞共培养。在 AML_3DON 龛下的 AML 细胞表现出更高的活力、减少的凋亡并保持 CD33 CD34 表型，与 AML_3DON 龛中抗凋亡细胞因子的高分泌相关。此外，AML_3DON 龛下的 AML 细胞对两种 FDA 批准的化疗药物的敏感性降低，进一步表明 AML_3DON 龛的生理相似性。最有趣的是，与健康_3DON 龛共培养的 AML 细胞对相同样本药物高度敏感。这项研究表明 AML 细胞对白血病和健康骨髓龛的不同反应，提示了天然癌细胞龛在药物筛选中的影响，以及分别在 AML 患者中重新构建健康骨髓龛作为化疗辅助剂克服化疗耐药的潜力。
