Genetic identification and functional dissection of the cellular interactome of haematopoietic stem cells and leukaemic stem cells

造血干细胞和白血病干细胞细胞相互作用组的遗传鉴定和功能解析

• 批准号: MR/V009222/1
• 负责人: Miguel Ganuza Fernandez
• 金额: $ 199.49万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV009222%2F1
• 关键词: Genetic; identification; functional; dissection; cellular

Blood stem cells (BSCs) produce all red and white blood cells that the body needs to survive and fight infection. BSCs sit in specialized pockets, so-called "niches" of cells in the bone marrow (BM). These niches are critical to regulate BSC health, and therefore help to generate all blood cells. The precise identity of the cells that form these niches is unknown. As we age, the environment that surrounds BSCs changes, and this can lead to health issues including anaemia or a weaker immune system. Moreover, if BSCs are damaged they can transform into leukaemic stem cells (LSCs). LSCs are able to further modify BM niches for their own benefit to promote cancer progression. Thus, it is very important to know exactly how the BM environment changes with age or disease so we can prevent and treat associated conditions, such as leukaemia.BSCs are used in BM transplantation to treat different blood diseases including leukaemia, anaemia, or sickle cell disease. Patients also need them to recover from anti-cancer treatments such as chemotherapy. Every year worldwide, thousands of people require a BM transplant. For the transplant to be successful, the donor has to be compatible with the recipient. Due to donor shortages, this can leave some patients without the transplant they need. To eliminate the continuous need of BM donors, scientists aim to expand BSCs in the laboratory, as this will lead to never-ending supply of suitable donor cells. Unfortunately, this is currently not possible as BSCs cannot be efficiently expanded in the laboratory. BSCs naturally divide in our bodies during infancy, but once we reach adulthood, they rarely divide. As such, our research begins with studying how BSCs expand during infancy. If we learn about how BSCs divide naturally within the body, we will be able to imitate this in the laboratory to get continuous supplies for BM transplants. Additionally, the precise composition of the niches that support leukaemic stem cells is also unknown. LSCs produce large numbers of immature cells, known as blasts, which rapidly divide, and interfere normal blood cell function. Chemotherapy is able to kill these blasts, but sometimes does not eradicate all the LSCs. Following therapy, the remaining LSCs are thought to fuel disease relapses. Since LSCs rely on their niches which nurture them, an alternative therapeutic approach is to cut off the lifeline of LSCs by targeting their niche cells. Hence, I aim to: 1) identify the niches that support healthy BSCs; and 2) reveal the niche components that are altered during ageing and that support LSCs during leukaemia. By understanding the differences between health and disease states we can develop therapies to prevent cancer emergence, and treat and cure patients. Notably, this area of research has been explored world-wide due to its high clinical interest. Although scientific advances have been made, current technologies lack the required precision to identify and isolate the niche cells. My research focuses around a technology that allows to fluorescently mark niche cells that are in physical contact with the BSCs or LSCs. Once the niche cells are labelled, we can isolate these cells from the bone marrow, with significantly more precision than the most skillful surgeon. We can then study these niche cells at the molecular level, and reveal how these niche cells change during development, adulthood, ageing and disease, including leukaemia. In sum, this research is of critical scientific and clinical importance and will result in: 1) eradication of LSCs, avoiding leukaemia relapses, 2) treating the effects of ageing on blood, 3) the expansion of BSCs in laboratory culture dishes for transplantation, which will decrease the need for bone marrow donors and will allow for the investigation of other blood diseases.

血液干细胞（BSC）产生人体生存和抵抗感染所需的所有红细胞和白细胞。 BSC 位于专门的口袋中，即骨髓 (BM) 中所谓的细胞“壁龛”。这些生态位对于调节 BSC 健康至关重要，因此有助于生成所有血细胞。形成这些生态位的细胞的确切身份尚不清楚。随着年龄的增长，BSC 周围的环境会发生变化，这可能会导致贫血或免疫系统较弱等健康问题。此外，如果 BSC 受损，它们可以转化为白血病干细胞 (LSC)。 LSC 能够为了自身利益进一步修改 BM 生态位，从而促进癌症进展。因此，准确了解骨髓环境如何随年龄或疾病而变化非常重要，这样我们就可以预防和治疗相关疾病，例如白血病。BSC 用于骨髓移植来治疗不同的血液疾病，包括白血病、贫血或镰状细胞病。患者还需要它们从化疗等抗癌治疗中恢复过来。全世界每年都有成千上万的人需要进行骨髓移植。为了移植成功，捐赠者必须与接受者相容。由于捐赠者短缺，这可能导致一些患者无法获得所需的移植。为了消除对骨髓供体的持续需求，科学家们的目标是在实验室中扩大BSC，因为这将导致源源不断的合适供体细胞的供应。不幸的是，目前这是不可能的，因为平衡计分卡无法在实验室中有效扩展。在婴儿期，BSC 在我们体内自然分裂，但一旦我们进入成年期，它们就很少分裂。因此，我们的研究从研究 BSC 在婴儿期如何扩展开始。如果我们了解 BSC 如何在体内自然分裂，我们将能够在实验室中模仿这一过程，为骨髓移植获得持续的供应。此外，支持白血病干细胞的生态位的精确组成也是未知的。 LSC 产生大量未成熟细胞（称为原始细胞），它们会快速分裂并干扰正常的血细胞功能。化疗能够杀死这些原始细胞，但有时并不能根除所有 LSC。治疗后，剩余的 LSC 被认为会加剧疾病复发。由于 LSC 依赖其微环境来滋养它们，因此另一种治疗方法是通过靶向其微环境细胞来切断 LSC 的生命线。因此，我的目标是：1）确定支持健康平衡计分卡的利基； 2) 揭示在衰老过程中发生改变并在白血病过程中支持 LSC 的生态位成分。通过了解健康状态和疾病状态之间的差异，我们可以开发预防癌症出现、治疗和治愈患者的疗法。值得注意的是，由于其高度的临床兴趣，该研究领域已在全世界范围内进行探索。尽管科学已经取得了进步，但当前的技术缺乏识别和分离利基细胞所需的精度。我的研究重点是一种能够对与 BSC 或 LSC 物理接触的利基细胞进行荧光标记的技术。一旦标记了利基细胞，我们就可以从骨髓中分离出这些细胞，其精度比最熟练的外科医生要高得多。然后我们可以在分子水平上研究这些利基细胞，并揭示这些利基细胞在发育、成年、衰老和疾病（包括白血病）过程中如何变化。总之，这项研究具有至关重要的科学和临床意义，将导致：1）根除LSC，避免白血病复发，2）治疗衰老对血液的影响，3）在实验室培养皿中扩增BSC进行移植，这将减少对骨髓捐献者的需求，并允许研究其他血液疾病。

项目成果

Specification of hematopoietic stem cells in mammalian embryos: a rare or frequent event?

哺乳动物胚胎中造血干细胞的规格：罕见还是常见事件？

• DOI: 10.1182/blood.2020009839
• 发表时间: 2022
• 期刊: Blood
• 影响因子: 20.3
• 作者: Ganuza M

Murine foetal liver supports limited detectable expansion of life-long haematopoietic progenitors.

• DOI: 10.1038/s41556-022-00999-5
• 发表时间: 2022-10
• 期刊: Nature cell biology
• 影响因子: 21.3

Diversity in the bone marrow niche: Classic and novel strategies to uncover niche composition.

• DOI: 10.1111/bjh.18355
• 发表时间: 2022-12
• 期刊: BRITISH JOURNAL OF HAEMATOLOGY
• 影响因子: 6.5
• 作者: Sanchez-Lanzas, Raul;Kalampalika, Foteini;Ganuza, Miguel
• 通讯作者: Ganuza, Miguel