Differential Effects of Heparin and Hyaluronic Acid on Neural Patterning of Human Induced Pluripotent Stem Cells
Differential Effects of Heparin and Hyaluronic Acid on Neural Patterning of Human Induced Pluripotent Stem Cells
复制标题
DOI：
10.1021/acsbiomaterials.8b01142
复制
发表时间：
2018-12-01
影响因子：
5.8
通讯作者：
Li, Yan
中科院分区：
文献类型：
--
作者：
Bejoy, Julie;Wang, Zhe;Li, Yan
缺乏可以有效地代表人脑病理学的良好建立的动物模型导致了人诱导多能干细胞（hiPSC）衍生的脑组织的开发。脑类器官增强了我们理解发育中的人脑和脑疾病的能力（例如，精神分裂症，小头畸形），但类器官仍然不能准确地概括人类大脑的解剖组织。因此，重要的是评估和优化诱导和信号传导因子，以工程化下一代脑类器官。在这项研究中，评估了透明质酸（HA）（一种通过配体结合受体与细胞相互作用的主要脑细胞外基质（ECM）组分）对hiPSC脑类器官模式化的影响。为了介导信号分子的HA结合能力，除了HA之外还加入肝素或与HA缀合以形成水凝胶（具有两种不同的模量）。用HA或肝素加HA（Hep-HA）处理源自hiPSC的神经皮质球状体，并分析ECM对神经模式化的影响。结果表明，Hep-HA对hiPSC衍生的神经球状体具有尾化作用，特别是对于刚性Hep-HA水凝胶。调节Wnt和Hippo/Yes相关蛋白（雅普）信号传导（分别使用Wnt抑制剂IVVP 4或肌动蛋白破坏剂细胞松弛素D）以了解潜在的机制。IVVP 4和细胞松弛素D促进前脑身份。这项研究的结果应该加强对仿生ECM因素对脑类器官生成的影响的理解。
A lack of well -established animal models that can efficiently represent human brain pathology has led to the development of human induced pluripotent stem cell (hiPSC)-derived brain tissues. Brain organoids have enhanced our ability to understand the developing human brain and brain disorders (e.g., Schizophrenia, microcephaly), but the organoids still do not accurately recapitulate the anatomical organization of the human brain. Therefore, it is important to evaluate and optimize induction and signaling factors in order to engineer the next generation of brain organoids. In this study, the impact of hyaluronic acid (HA), a major brain extracellular matrix (ECM) component that interacts with cells through ligand-binding receptors, on the patterning of brain organoids from hiPSCs was evaluated. To mediate HA binding capacity of signaling molecules, heparin was added in addition to HA or conjugated to HA to form hydrogels (with two different moduli). The neural cortical spheroids derived from hiPSCs were treated with either HA or heparin plus HA (Hep-HA) and were analyzed for ECM impacts on neural patterning. The results indicate that Hep-HA has a caudalizing effect on hiPSC-derived neural spheroids, in particular for stiff Hep-HA hydrogels. Wnt and Hippo/Yes-associated protein (YAP) signaling was modulated (using Wnt inhibitor IVVP4 or actin disruption agent Cytochalasin D respectively) to understand the underlying mechanism. IVVP4 and cytochalasin D promote forebrain identity. The results from this study should enhance the understanding of influence of biomimetic ECM factors for brain organoid generation.