Scala Pasqualina, Serio Bianca, Giudice Valentina
Department of Medicine, Surgery, and Dentistry, University of Salerno, Baronissi 84081, Italy.
Hematology and Transplant Center, University Hospital "San Giovanni di Dio e Ruggi d'Aragona", Salerno 84131, Italy.
ACS Biomater Sci Eng. 2026 Jan 12;12(1):110-127. doi: 10.1021/acsbiomaterials.5c01421. Epub 2025 Dec 12.
The bone marrow niche is a specialized microenvironment sustaining a hematopoietic stem cell (HSC) pool and regulating the production of mature blood cells. Its exact composition and mechanisms remain incompletely defined, mainly due to the lack of models that accurately reproduce its physiological three-dimensional (3D) architecture and cellular crosstalk. Two-dimensional cultures fail to sustain HSC quiescence and stemness, while advanced 3D systems can reproduce key structural and mechanism cues of the niche. In this review, we first describe physiological cellular, stromal, and matrix components of the bone marrow niche, highlighting their coordinated regulation of HSC maintenance, proliferation, and mobilization. We then critically examine current approaches for 3D bone marrow models, including scaffold-based methods, decellularized models, spheroid and organoid systems, 3D bioprinting applications, and organ-on-chip technologies, discussing their advances, limitations, and potential disease modeling in this field. Finally, we outline how these technologies could deepen our understanding of hematopoiesis mechanisms, clonal evolution, and niche-mediated drug resistance. We also highlight the pros and cons of each methodology and future directions toward standardized protocols, integrating tissue components, and the use of human cells to enhance reproducibility and clinical relevance. Advances like bone marrow-on-a-chip, computational models, and patient-specific systems will help bridge the gap between and studies, enabling drug testing, stem cell expansion, and gene editing strategies, including chimeric antigen receptor expression. Bone marrow models have evolved from simple 2D cultures to advanced 3D and organ-on-a-chip systems, significantly improving our understanding of hematopoiesis and accelerating new therapies.
骨髓微环境是一种特殊的微环境，它维持着造血干细胞（HSC）库，并调节成熟血细胞的生成。其确切组成和机制仍未完全明确，主要是由于缺乏能够准确再现其生理三维（3D）结构和细胞间相互作用的模型。二维培养无法维持造血干细胞的静止状态和干性，而先进的三维系统可以再现微环境的关键结构和机制线索。在这篇综述中，我们首先描述骨髓微环境的生理细胞、基质和基质成分，强调它们对造血干细胞维持、增殖和动员的协调调节。然后，我们批判性地审视当前三维骨髓模型的方法，包括基于支架的方法、去细胞模型、球体和类器官系统、三维生物打印应用和芯片器官技术，讨论它们在该领域的进展、局限性和潜在的疾病建模。最后，我们概述这些技术如何加深我们对造血机制、克隆进化和微环境介导的耐药性的理解。我们还强调了每种方法的优缺点以及朝着标准化方案、整合组织成分和使用人类细胞以提高可重复性和临床相关性的未来方向。像芯片骨髓、计算模型和患者特异性系统这样的进展将有助于弥合基础研究和临床研究之间的差距，实现药物测试、干细胞扩增和基因编辑策略，包括嵌合抗原受体表达。骨髓模型已经从简单的二维培养发展到先进的三维和芯片器官系统，显著提高了我们对造血的理解并加速了新疗法的研发。
