Greene Gretchen, Pothayee Nikorn, Jahanipour Jahandar, Jie Hyesoo, Tao-Cheng Jung-Hwa, Petrus Emily, Maric Dragan, Koretsky Alan P
Laboratory of Functional and Molecular Imaging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
Flow and Imaging Cytometry Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States.
Front Cell Dev Biol. 2025 Jul 3;13:1577045. doi: 10.3389/fcell.2025.1577045. eCollection 2025.
There has been renewed interest in neural transplantation of cells and tissues for brain repair. Recent studies have demonstrated the ability of transplanted neural precursor cells and grown organoids to mature and locally integrate into host brain circuitry. Most studies have focused on how the transplant behaves and functions after the procedure, but the extent to which the host brain can properly innervate the transplant, particularly in the context of aging, is largely unexplored. Here we report that transplantation of rat embryonic cortical precursor cells into the cerebrospinal fluid-subventricular zone (CSF-SVZ) interface of adult rat brains generates a brain-like tissue (BLT) at an ectopic site. This model allows for the assessment of precursor cell development, cellular interactions, and graft-host connectivity as a function of host age. We found that the transplanted precursor cells initially proliferated, then differentiated, and developed into mature BLTs, which received supportive cellular components from the host including blood vessels, microglia, astrocytes, and oligodendrocytes. There was integration of the BLT into the host brain which occurred at all ages studied, suggesting that host age does not affect the maturation and integration of the precursor cell-derived BLT. Long-range axonal projections from the BLT into the host brain were robust throughout the different aged recipients. However, long-distance innervation originating from the host brain into the BLT significantly declined with age. This work demonstrates the feasibility and utility of integrating new neural tissue structures at ectopic sites into adult brain circuits to study host-transplant interactions.
细胞和组织的神经移植用于脑修复已重新引起人们的关注。最近的研究表明，移植的神经前体细胞和培养的类器官能够成熟并局部整合到宿主脑回路中。大多数研究都集中在移植术后的行为和功能上，但宿主脑能够正确支配移植组织的程度，尤其是在衰老的情况下，在很大程度上尚未得到探索。在此，我们报告将大鼠胚胎皮质前体细胞移植到成年大鼠脑的脑脊液 - 脑室下区（CSF - SVZ）界面，在异位部位产生了类似脑的组织（BLT）。该模型允许评估前体细胞发育、细胞相互作用以及作为宿主年龄函数的移植物 - 宿主连接性。我们发现，移植的前体细胞最初增殖，然后分化，并发育成成熟的BLT，其从宿主接收包括血管、小胶质细胞、星形胶质细胞和少突胶质细胞在内的支持性细胞成分。BLT在所有研究的年龄阶段都整合到宿主脑中，这表明宿主年龄不影响前体细胞衍生的BLT的成熟和整合。在不同年龄的受体中，从BLT到宿主脑的长距离轴突投射都很强大。然而，从宿主脑到BLT的长距离神经支配随着年龄的增长显著下降。这项工作证明了将异位部位的新神经组织结构整合到成年脑回路中以研究宿主 - 移植相互作用的可行性和实用性。
