英国威康桑格研究所Peter J. Campbell等研究人员合作揭示同种异体造血细胞移植后的克隆动态。相关论文于2024年10月30日在线发表在《自然》杂志上。

为了量化长期干细胞植入的动态，研究人员对来自10对供体-受体的2824个单细胞衍生的造血克隆进行了基因组测序，这些样本是在HLA配对的兄弟姐妹造血细胞移植（HCT）后9至31年采集的。对于较年轻的供体（在移植时年龄为18至47岁），有5000至30000个干细胞成功植入，并在采样时仍对造血有所贡献；而对于较老的供体（50至66岁），这个估计数值低十倍。

植入的细胞在髓系、B淋巴和T淋巴群体中均有多系贡献，尽管个别克隆往往对某一成熟细胞类型表现出偏好。受体的克隆多样性低于匹配的供体，相当于约10至15年的额外老化，这源于干细胞克隆的扩增高达25倍。移植相关的群体瓶颈无法解释这些差异；相反，系统发育树显示出两种不同的HCT特异性选择模式。

在修剪选择中，支持受体富集克隆扩增的细胞分裂发生在供体中，发生在移植之前，其选择优势源于优先动员、收集、体外存活或最初归巢。在生长选择中，支持克隆扩增的细胞分裂发生在受体的骨髓中，最明显的是在具有多个驱动突变的克隆中。与供体的未干扰造血相比，将干细胞从其原生环境中移除并移植到异体环境加剧了选择压力，扭曲并加速了克隆多样性的丧失。

研究人员表示，同种异体HCT通过用供体的干细胞替代负责血液生成的干细胞。

附：英文原文

Title: Clonal dynamics after allogeneic haematopoietic cell transplantation

Author: Spencer Chapman, Michael, Wilk, C. Matthias, Boettcher, Steffen, Mitchell, Emily, Dawson, Kevin, Williams, Nicholas, Mller, Jan, Kovtonyuk, Larisa, Jung, Hyunchul, Caiado, Francisco, Roberts, Kirsty, ONeill, Laura, Kent, David G., Green, Anthony R., Nangalia, Jyoti, Manz, Markus G., Campbell, Peter J.

Issue&Volume: 2024-10-30

Abstract: Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those from a donor1,2. Here, to quantify dynamics of long-term stem cell engraftment, we sequenced genomes from 2,824 single-cell-derived haematopoietic colonies of ten donor–recipient pairs taken 9–31years after HLA-matched sibling HCT3. With younger donors (18–47 years at transplant), 5,000–30,000 stem cells had engrafted and were still contributing to haematopoiesis at the time of sampling; estimates were tenfold lower with older donors (50–66 years). Engrafted cells made multilineage contributions to myeloid, B lymphoid and T lymphoid populations, although individual clones often showed biases towards one or other mature cell type. Recipients had lower clonal diversity than matched donors, equivalent to around 10–15 years of additional ageing, arising from up to 25-fold greater expansion of stem cell clones. A transplant-related population bottleneck could not explain these differences; instead, phylogenetic trees evinced two distinct modes of HCT-specific selection. In pruning selection, cell divisions underpinning recipient-enriched clonal expansions had occurred in the donor, preceding transplant—their selective advantage derived from preferential mobilization, collection, survival ex vivo or initial homing. In growth selection, cell divisions underpinning clonal expansion occurred in the recipient’s marrow after engraftment, most pronounced in clones with multiple driver mutations. Uprooting stem cells from their native environment and transplanting them to foreign soil exaggerates selective pressures, distorting and accelerating the loss of clonal diversity compared to the unperturbed haematopoiesis of donors.

DOI: 10.1038/s41586-024-08128-y

Source: https://www.nature.com/articles/s41586-024-08128-y