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

血液干细胞（BSCs）产生人体生存和抵抗感染所需的所有红细胞和白细胞。骨髓间充质干细胞位于专门的口袋中，即骨髓中所谓的细胞“壁龛”。这些壁龛对调节BSC健康至关重要，因此有助于产生所有血细胞。形成这些壁龛的细胞的确切身份尚不清楚。随着年龄的增长，BSCs周围的环境会发生变化，这可能导致贫血或免疫系统变弱等健康问题。此外，如果BSCs受损，它们可以转化为白血病干细胞（LSCs）。LSCs能够为了自身的利益而进一步修改BM利基，从而促进癌症的进展。因此，确切了解脑脊膜环境如何随年龄或疾病变化是非常重要的，这样我们就可以预防和治疗相关疾病，如白血病。BSCs在骨髓移植中用于治疗不同的血液疾病，包括白血病、贫血或镰状细胞病。患者也需要它们从化疗等抗癌治疗中恢复过来。每年全世界都有成千上万的人需要骨髓移植。为了使移植成功，供体必须与受体相容。由于供体短缺，这可能会导致一些患者无法进行所需的移植手术。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骨髓间充质干细胞，因为这将导致合适的供体细胞源源不断的供应。不幸的是，目前这是不可能的，因为BSCs不能在实验室中有效地扩增。在婴儿时期，BSCs在我们体内自然分裂，但一旦我们成年，它们就很少分裂了。因此，我们的研究从研究婴儿期BSCs如何扩张开始。如果我们了解骨髓间充质干细胞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，为骨髓移植提供持续的供应。此外，支持白血病干细胞的小生境的精确组成也是未知的。LSCs产生大量未成熟的细胞，称为胚细胞，这些细胞迅速分裂，并干扰正常的血细胞功能。化疗能够杀死这些细胞，但有时不能根除所有的LSCs。治疗后，剩余的LSCs被认为会加剧疾病复发。由于LSCs依赖于培育它们的小生境，另一种治疗方法是通过靶向LSCs的小生境细胞来切断LSCs的生命线。因此，我的目标是：1)确定支持健康BSCs的利基；2)揭示在衰老过程中改变的利基成分，以及在白血病期间支持LSCs的利基成分。通过了解健康和疾病状态之间的差异，我们可以开发出预防癌症出现的疗法，并治疗和治愈患者。值得注意的是，由于其高度的临床兴趣，这一研究领域已在世界范围内进行了探索。尽管科学已经取得了进步，但目前的技术缺乏识别和分离生态位细胞所需的精度。我的研究重点是一种技术，可以荧光标记与BSCs或LSCs物理接触的小生境细胞。一旦定位细胞被标记，我们就可以从骨髓中分离出这些细胞，比最熟练的外科医生要精确得多。然后，我们可以在分子水平上研究这些生态位细胞，并揭示这些生态位细胞在发育、成年、衰老和疾病（包括白血病）期间是如何变化的。总之，这项研究具有重要的科学和临床意义，并将导致：1)根除LSCs，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大BSCs用于移植，这将减少对骨髓供体的需求，并将允许研究其他血液疾病。

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.