Improving haematopoietic reconstitution in blood stem cell transplantation procedures through the regulation of stem cells and their niches

通过干细胞及其生态位的调节改善血液干细胞移植过程中的造血重建

• 批准号: MR/V005421/1
• 负责人: Simon Mendez-Ferrer
• 金额: $ 80.9万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV005421%2F1
• 关键词: Improving; haematopoietic; reconstitution; blood; stem

Blood production is tightly controlled by the interactions of blood-forming stem cells residing inside the bones (in the bone marrow) with distinct specialised microenvironments, called niches. The niche cells protect blood forming stem cells from damage and maintain their potential to produce blood and immune cells throughout life. The applicant teams have contributed to dissect blood stem cells, their niches and their functional alterations in blood cancers.Blood stem cell transplantation is routinely performed for lifesaving procedures in patients with blood cancers or inherited metabolic/immune disorders. Different blood stem cell sources, such as bone marrow, the peripheral blood, and cord blood are used for allogeneic transplantation. The use of cord blood presents several advantages, such as easy and noninvasive harvest, reduced risk of disease transmission, immediate availability of cryopreserved units and increased immune tolerance. However, the limited number of blood stem cells present in each cord blood has restricted its use to low-body-weight recipients (mostly children). Moreover, the recovery of the blood and immune system and the overall survival after cord blood transplantation correlates with the number of blood stem cells transplanted.Regenerating normal blood production in the bone marrow of transplanted patients after requires:1) Harvest of blood stem cells from donors in sufficient numbers.2) Optimal migration and lodgement of transplanted blood stem cells in the bone marrow niches of transplanted recipients and3) Expansion of engrafted blood stem cells and production of multiple blood and immune cells.However,A) On the donor side, due to the low blood stem cell number available in each cord blood unit, several cord units are necessary for transplantation and the HSC engraftment is delayed (compared with other blood stem cell sources, such as bone marrow or blood stem cells mobilised from the bone marrow to the peripheral blood).B) On the recipient side (niche), the efficacy of blood stem cell engraftment significantly decreases during ageing, hampering the use of blood stem cell transplantation as a therapeutic option in many cases.This proposal aims at understanding and modelling the regeneration process following blood stem cell transplantation. The main goal is to identify mechanisms controlling the engraftment and the expansion of blood stem cells after transplantation, and the subsequent production of blood and immune cells necessary for bone marrow regeneration. Our translational aim is instructing blood stem cells to more efficiently/rapidly/long-lastingly regenerate the blood and immune systems.To investigate the process of bone marrow regeneration we will transplant human umbilical cord blood into genetically-modified mice which lack a functional immune system and therefore do no reject the human cells, allowing for the engraftment of human blood stem cells. Additionally, an artificial niche will be created allowing for the engraftment of human blood stem cells and human niche cells to model the human system. This joint project will enable a unique synergy between the 4 applicants with expertise in the cellular and molecular heterogeneity of human blood stem cells (Laurenti), their regulation through inflammatory factors (Takizawa), cellular metabolism (Suda) and microenvironmental cues (Mendez-Ferrer). The complementary expertise of the four teams could facilitate overcoming current limitations in HSC transplantation procedures.

血液的产生受到骨内造血干细胞（在骨髓中）与特殊微环境（称为壁龛）的相互作用的严格控制。生态位细胞保护造血干细胞免受损害，并维持其在一生中产生血液和免疫细胞的潜力。申请团队对解剖血液干细胞、它们的壁龛和它们在血癌中的功能改变做出了贡献。血液干细胞移植是血癌或遗传性代谢/免疫疾病患者的常规救命手术。不同的造血干细胞来源，如骨髓、外周血和脐带血用于同种异体移植。使用脐带血有几个优点，例如容易和无创的收获，降低疾病传播的风险，立即获得冷冻保存单位和提高免疫耐受性。然而，每种脐带血中存在的有限数量的造血干细胞限制了其用于低体重受体（主要是儿童）。此外，脐带血移植后血液和免疫系统的恢复以及整体存活率与移植的造血干细胞数量有关。移植患者的骨髓再生需要：1)从供体获取足够数量的造血干细胞。2)移植造血干细胞在移植受者骨髓壁龛中的最佳迁移和安置；3)移植造血干细胞的扩增和多种血液细胞和免疫细胞的产生。然而，A)在供体方面，由于每个脐带血单位中可用的血液干细胞数量较低，移植需要几个脐带血单位，并且HSC移植延迟（与其他血液干细胞来源相比，如骨髓或从骨髓动员到外周血的血液干细胞）。B)在受体方面（利基），随着年龄的增长，血液干细胞移植的疗效显著下降，在许多情况下阻碍了将血液干细胞移植作为一种治疗选择。本研究旨在理解和模拟造血干细胞移植后的再生过程。主要目标是确定控制移植后血液干细胞的植入和扩增的机制，以及随后骨髓再生所需的血液和免疫细胞的产生。我们的翻译目标是指导血液干细胞更有效/快速/持久地再生血液和免疫系统。为了研究骨髓再生的过程，我们将把人类脐带血移植到缺乏功能性免疫系统的转基因小鼠体内，因此不会排斥人类细胞，从而允许人类血液干细胞的移植。此外，将创建一个人工生态位，允许植入人类血液干细胞和人类生态位细胞来模拟人类系统。该联合项目将使4名申请人在人类血液干细胞的细胞和分子异质性（Laurenti），通过炎症因子（Takizawa），细胞代谢（Suda）和微环境线索（Mendez-Ferrer）的调节方面具有独特的协同作用。四个团队的互补专业知识可以促进克服当前HSC移植手术的局限性。

项目成果

Cholinergic signals preserve haematopoietic stem cell quiescence during regenerative haematopoiesis.

• DOI: 10.1038/s41467-022-28175-1
• 发表时间: 2022-01-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Fielding C;García-García A;Korn C;Gadomski S;Fang Z;Reguera JL;Pérez-Simón JA;Göttgens B;Méndez-Ferrer S
• 通讯作者: Méndez-Ferrer S

S250: CHOLINERGIC SIGNALS PROMOTE THE QUIESCENCE OF NORMAL OR LEUKAEMIC STEM CELLS THROUGH THE ACTIVATION OF ALPHA 7-NICOTINIC RECEPTOR IN BONE MARROW MESENCHYMAL STROMAL CELLS

S250：胆碱能信号通过激活骨髓间充质基质细胞中的 α 7-烟碱受体促进正常或白血病干细胞的静止

• DOI: 10.1097/01.hs9.0000843892.05252.aa
• 发表时间: 2022
• 期刊: HemaSphere
• 影响因子: 6.6
• 作者: Fielding C

Mesoderm-Derived PDGFRA + Cells Regulate the Emergence of Hematopoietic Stem Cells in the Dorsal Aorta

中胚层衍生的 PDGFRA 细胞调节背主动脉造血干细胞的出现

• DOI: 10.1101/2021.08.08.455592
• 发表时间: 2021
• 作者: Chandrakanthan V

Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.

• DOI: 10.1038/s41467-023-43175-5
• 发表时间: 2023-11-25
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Fang Z;Corbizi Fattori G;McKerrell T;Boucher RH;Jackson A;Fletcher RS;Forte D;Martin JE;Fox S;Roberts J;Glover R;Harris E;Bridges HR;Grassi L;Rodriguez-Meira A;Mead AJ;Knapper S;Ewing J;Butt NM;Jain M;Francis S;Clark FJ;Coppell J;McMullin MF;Wadelin F;Narayanan S;Milojkovic D;Drummond MW;Sekhar M;ElDaly H;Hirst J;Paramor M;Baxter EJ;Godfrey AL;Harrison CN;Méndez-Ferrer S
• 通讯作者: Méndez-Ferrer S

Neuronal regulation of bone marrow stem cell niches.

• DOI: 10.12688/f1000research.22554.1
• 发表时间: 2020-01-01
• 期刊: F1000Research
• 作者: Fielding, Claire;Mendez-Ferrer, Simon
• 通讯作者: Mendez-Ferrer, Simon