Bruschi Michela, Vanzolini Tania, Sahu Neety, Balduini Alessandra, Magnani Mauro, Fraternale Alessandra
Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, Italy.
Department of Orthopedic Surgery, School of Medicine, Stanford University, Stanford, CA, United States.
Front Bioeng Biotechnol. 2022 Aug 17;10:968086. doi: 10.3389/fbioe.2022.968086. eCollection 2022.
Hematopoietic stem cells (HSCs) reside in a subzone of the bone marrow (BM) defined as the hematopoietic niche where, the interplay of differentiation and self-renewal, they can give rise to immune and blood cells. Artificial hematopoietic niches were firstly developed in 2D cultures but the limited expansion potential and stemness maintenance induced the optimization of these systems to avoid the total loss of the natural tissue complexity. The next steps were adopted by engineering different materials such as hydrogels, fibrous structures with natural or synthetic polymers, ceramics, etc. to produce a 3D substrate better resembling that of BM. Cytokines, soluble factors, adhesion molecules, extracellular matrix (ECM) components, and the secretome of other niche-resident cells play a fundamental role in controlling and regulating HSC commitment. To provide biochemical cues, co-cultures, and feeder-layers, as well as natural or synthetic molecules were utilized. This review gathers key elements employed for the functionalization of a 3D scaffold that demonstrated to promote HSC growth and differentiation ranging from 1) biophysical cues, i.e., material, topography, stiffness, oxygen tension, and fluid shear stress to 2) biochemical hints favored by the presence of ECM elements, feeder cell layers, and redox scavengers. Particular focus is given to the 3D systems to recreate megakaryocyte products, to be applied for blood cell production, whereas HSC clinical application in such 3D constructs was limited so far to BM diseases testing.
造血干细胞（HSCs）存在于骨髓（BM）的一个特定区域，即造血龛，在那里，它们通过分化和自我更新的相互作用，可以产生免疫细胞和血细胞。人工造血龛最初是在二维培养中开发的，但有限的扩增潜力和干性维持促使对这些系统进行优化，以避免完全丧失天然组织的复杂性。接下来的步骤是通过设计不同的材料，如水凝胶、天然或合成聚合物的纤维结构、陶瓷等，来制造一种更类似于骨髓的三维基质。细胞因子、可溶性因子、黏附分子、细胞外基质（ECM）成分以及其他龛内驻留细胞的分泌组在控制和调节造血干细胞的定向分化中起着至关重要的作用。为了提供生化信号、共培养和饲养层，人们利用了天然或合成分子。本综述收集了用于三维支架功能化的关键要素，这些要素已证明能促进造血干细胞的生长和分化，范围从1）生物物理信号，即材料、形貌、硬度、氧张力和流体剪切应力，到2）由细胞外基质成分、饲养细胞层和氧化还原清除剂的存在所支持的生化信号。特别关注用于重建巨核细胞产物的三维系统，以应用于血细胞生产，而到目前为止，造血干细胞在这种三维构建体中的临床应用仅限于骨髓疾病测试。
