Neutral competition explains the clonal composition of neural organoids

Cerebral organoids model the development of the human brain and are an indispensable tool for studying neurodevelopment. Whole-organoid lineage tracing has revealed the number of progeny arising from each initial stem cell to be highly diverse, with lineage sizes ranging from one to more than 20,000 cells. This exceeds what can be explained by existing stochastic models of corticogenesis, indicating the existence of an additional source of stochasticity. We propose an explanation in terms of the SAN model in which this additional source of stochasticity is the survival time of a lineage within a long-lived population of symmetrically dividing cells under neutral competition. We demonstrate that this model explains the experimentally observed variability of lineage sizes and we derive a formula that captures the quantitative relationship between survival time and lineage size. Finally, we show that our model implies the existence of a regulatory mechanism to keeps the size of the symmetrically dividing cell population constant. Barcode-based Lineagetracing to measure the lineage size distribution in brain organoids in three replicates脑类器官（cerebral organoids）可模拟人类大脑发育进程，是神经发育研究领域不可或缺的实验工具。全类器官谱系示踪技术已证实，单个初始干细胞产生的子代细胞数量存在极高异质性，谱系规模跨度从1个细胞至20000余个细胞不等。该谱系规模的分布范围远超现有大脑皮层发生随机模型的解释范畴，提示存在额外的随机扰动来源。我们提出基于SAN模型的解释框架：该额外随机扰动来源，实为中性竞争环境下，对称分裂细胞长寿群体中单个谱系的存续时长。我们证实该模型可解释实验中观测到的谱系规模异质性，并推导出能够描述存续时长与谱系规模间定量关系的公式。最后，本研究表明该模型暗示存在一种调控机制，可维持对称分裂细胞群体的规模恒定。本数据集采用基于条形码的谱系示踪技术，在3次生物学重复实验中检测脑类器官内的谱系规模分布。