Table 2_Age-dependent integration of cortical progenitors transplanted at CSF-neurogenic niche interface.docx

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 in vitro 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.

当前，用于脑修复的细胞与组织神经移植（neural transplantation）再度引发研究兴趣。近期研究已证实，移植的神经前体细胞（neural precursor cells）及体外培养的类器官（organoids）能够成熟并局部整合至宿主脑环路（host brain circuitry）。多数现有研究聚焦于移植术后移植物的行为与功能，但宿主脑能够对移植物实施恰当神经支配的程度，尤其是在衰老背景下，这一问题仍未得到充分探索。在此，我们报道将大鼠胚胎皮质前体细胞移植至成年大鼠脑的脑脊液-室下区（CSF-SVZ）界面后，可在异位位点生成脑样组织（BLT）。该模型可用于评估与宿主年龄相关的前体细胞发育、细胞互作以及移植物-宿主连接（graft-host connectivity）情况。研究发现，移植的前体细胞先经历增殖、随后分化，最终发育为成熟的脑样组织；该组织可从宿主获取包括血管、小胶质细胞（microglia）、星形胶质细胞（astrocytes）以及少突胶质细胞（oligodendrocytes）在内的支持性细胞组分。在所研究的所有年龄组中，脑样组织均能整合至宿主脑，这提示宿主年龄不会影响前体细胞来源的脑样组织的成熟与整合过程。在不同年龄的受体脑中，脑样组织向宿主脑发出的长距离轴突投射（long-range axonal projections）均较为显著。然而，源自宿主脑向脑样组织的长距离神经支配（long-distance innervation）则随年龄增长显著减弱。本研究证实了在异位位点构建新型神经组织结构并整合至成年脑环路以研究宿主-移植物互作的可行性与应用价值。