During brain development, neural progenitors expand through symmetric divisions before giving rise to differentiating cell types via asymmetric divisions. Transition between those modes varies among individual neural stem cells, resulting in clones of different sizes. Imaging-based lineage tracing allows for lineage analysis at high cellular resolution but systematic approaches to analyse clonal behaviour of entire tissues are currently lacking. Here we implement whole-tissue lineage tracing by genomic DNA barcoding in 3D human cerebral organoids, to show that individual stem cell clones produce progeny on a vastly variable scale. By using stochastic modelling we find that variable lineage sizes arise because a subpopulation of lineages retains symmetrically dividing cells. We show that lineage sizes can adjust to tissue demands after growth perturbation via chemical ablation or genetic restriction of a subset of cells in chimeric organoids. Our data suggest that adaptive plasticity of stem cell populations ensures robustness of development in human brain organoids.

在大脑发育过程中，神经祖细胞通过对称分裂扩展，然后通过不对称分裂产生分化的细胞类型。这些模式之间的转换因个体神经干细胞而异，从而产生不同大小的克隆。基于成像的谱系追踪允许以高细胞分辨率进行谱系分析，但目前缺乏分析整个组织克隆行为的系统方法。在这里，我们通过 3D 人类大脑类器官中的基因组 DNA 条形码进行全组织谱系追踪，以表明单个干细胞克隆以巨大的可变规模产生后代。通过使用随机模型，我们发现谱系大小会出现变化，因为谱系亚群保留了对称分裂的细胞。我们表明，通过化学消融或嵌合类器官中细胞子集的遗传限制，谱系大小可以在生长扰动后适应组织需求。我们的数据表明，干细胞群的适应性可塑性确保了人脑类器官发育的稳健性。