Del Rosario Ricardo C H, Krienen Fenna M, Zhang Qiangge, Goldman Melissa, Mello Curtis, Lutservitz Alyssa, Ichihara Kiku, Wysoker Alec, Nemesh James, Feng Guoping, McCarroll Steven A
Department of Genetics, Harvard Medical School, Boston, MA 02115.
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
bioRxiv. 2023 Oct 17:2023.10.16.562516. doi: 10.1101/2023.10.16.562516.
Chimerism happens rarely among most mammals but is common in marmosets and tamarins, a result of fraternal twin or triplet birth patterns in which connected circulatory systems (through which stem cells transit) lead to persistent blood chimerism (12-80%) throughout life. The presence of Y-chromosome DNA sequences in other organs of female marmosets has long suggested that chimerism might also affect these organs. However, a longstanding question is whether this chimerism is driven by blood-derived cells or involves contributions from other cell types. To address this question, we analyzed single-cell RNA-seq data from blood, liver, kidney and multiple brain regions across a number of marmosets, using transcribed single nucleotide polymorphisms (SNPs) to identify cells with the sibling's genome in various cell types within these tissues. Sibling-derived chimerism in all tissues arose entirely from cells of hematopoietic origin (i.e., myeloid and lymphoid lineages). In brain tissue this was reflected as sibling-derived chimerism among microglia (20-52%) and macrophages (18-64%) but not among other resident cell types (i.e., neurons, glia or ependymal cells). The percentage of microglia that were sibling-derived showed significant variation across brain regions, even within individual animals, likely reflecting distinct responses by siblings' microglia to local recruitment or proliferation cues or, potentially, distinct clonal expansion histories in different brain areas. In the animals and tissues we analyzed, microglial gene expression profiles bore a much stronger relationship to local/host context than to sibling genetic differences. Naturally occurring marmoset chimerism will provide new ways to understand the effects of genes, mutations and brain contexts on microglial biology and to distinguish between effects of microglia and other cell types on brain phenotypes.
嵌合体现象在大多数哺乳动物中很少见，但在狨猴和绢毛猴中很常见，这是异卵双胞胎或三胞胎出生模式的结果，即相连的循环系统（干细胞通过该系统转运）导致终生持续的血液嵌合体（12% - 80%）。长期以来，雌性狨猴其他器官中Y染色体DNA序列的存在表明嵌合体现象可能也会影响这些器官。然而，一个长期存在的问题是，这种嵌合体是由血液来源的细胞驱动的，还是涉及其他细胞类型的贡献。为了解决这个问题，我们分析了来自多个狨猴的血液、肝脏、肾脏和多个脑区的单细胞RNA测序数据，利用转录的单核苷酸多态性（SNP）来识别这些组织中不同细胞类型中具有同胞基因组的细胞。所有组织中的同胞来源嵌合体完全来自造血起源的细胞（即髓系和淋巴系）。在脑组织中，这表现为小胶质细胞（20% - 52%）和巨噬细胞（18% - 64%）中有同胞来源的嵌合体，但在其他驻留细胞类型（即神经元、神经胶质细胞或室管膜细胞）中没有。同胞来源的小胶质细胞百分比在不同脑区甚至在个体动物体内都有显著差异，这可能反映了同胞小胶质细胞对局部招募或增殖信号的不同反应，或者可能反映了不同脑区不同的克隆扩增历史。在我们分析的动物和组织中，小胶质细胞的基因表达谱与局部/宿主环境的关系比与同胞基因差异的关系更为密切。自然发生的狨猴嵌合体现象将为理解基因、突变和脑环境对小胶质细胞生物学的影响，以及区分小胶质细胞和其他细胞类型对脑表型的影响提供新的方法。
