Functional compensation between hematopoietic stem cell clones in vivo

In most organ systems, regeneration is a coordinated effort that involves many stem cells, but little is known about whether and how individual stem cells compensate for the differentiation deficiencies of other stem cells. Functional compensation is critically important during disease progression and treatment. Here, we show how individual hematopoietic stem cell (HSC) clones heterogeneously compensate for the lymphopoietic deficiencies of other HSCs in a mouse. This compensation rescues the overall blood supply and influences blood cell types outside of the deficient lineages in distinct patterns. We find that highly differentiating HSC clones expand their cell numbers at specific differentiation stages to compensate for the deficiencies of other HSCs. Some of these clones continue to expand after transplantation into secondary recipients. In addition, lymphopoietic compensation involves gene expression changes in HSCs that are characterized by increased lymphoid priming, decreased myeloid priming and HSC self-renewal. Our in vivo small molecule screen identified small molecules that can alter the capacity of HSCs to compensate for lineage deficiency. Our data illustrate how HSC clones coordinate to maintain the overall blood supply. Exploiting the innate compensation capacity of stem cell networks may improve the prognosis and treatment of many diseases.

在绝大多数器官系统中，再生是一项涉及众多干细胞的协同过程，但目前对于单个干细胞是否能够、以及如何代偿其他干细胞的分化缺陷，仍知之甚少。功能代偿在疾病进程与治疗过程中至关重要。本研究揭示了小鼠体内单个造血干细胞（hematopoietic stem cell, HSC）克隆如何异质性地代偿其他HSC的淋巴细胞生成缺陷。此类代偿可挽救整体血液供给，并以独特模式影响缺陷谱系之外的血细胞类型。研究发现，高分化潜能的HSC克隆可在特定分化阶段扩增细胞数量，以此代偿其他HSC的功能缺陷。部分此类克隆在移植至次级受体后仍可持续扩增。此外，淋巴细胞生成代偿涉及HSC的基因表达改变，其特征为淋巴系预置增强、髓系预置减弱以及HSC自我更新能力的改变。我们通过体内小分子筛选实验，鉴定出可改变HSC代偿谱系缺陷能力的小分子化合物。本研究数据阐明了HSC克隆如何协同维持整体血液供给稳态。利用干细胞网络的固有代偿能力，或可改善多种疾病的预后与治疗策略。