Review: How do novel technologies advance the knowledge into blood formation during development?

Blood stem cells, also called hematopoietic stem cells (HSCs), are generated during embryonic development. They are responsible for the production of all mature blood cells throughout life. Transplantation of HSCs from healthy donors is often the only curative therapy for patients with blood-related diseases. Currently, there is a major shortage of compatible donor HSCs and despite decades of intense research to find an alternative source, it is still not possible to generate HSCs in the lab. Understanding how cells transform into functional HSCs in living organisms (i.e., in vivo) is imperative to be able to reproduce the process in laboratories.

The aorta: the cradle of hematopoietic stem cells

The origin of HSCs lies within the early developing vertebrate embryo. More precisely, all HSCs are generated from specialized cells embedded in the wall of the aorta, called hemogenic endothelial cells. These cells progressively differentiate into HSC precursors that further mature into HSCs. To be functional, HSCs need to acquire the capacity to differentiate to produce all short-life mature blood cells. Additionally, HSCs also need to acquire self-renewal capacities to maintain a constant pool of HSCs throughout life.

Researchers now start to understand that the aorta offers a unique niche which secretes growth factors and/or directly interacts with HSC precursors to activate complex processes essential for the formation of functional HSCs in vivo. A better understanding of the context and consequences of this cross-talk is crucial for creating a surrogate aortic environment or at least incorporating its key components in culture to promote HSC production in the lab.

Genetic approaches to study the aortic niche

Various interacting signals from the aortic niche, as well as biomechanical forces, form an intricate signaling network that regulates the formation of HSCs. These signaling events are far from fully understood and many questions remain open, such as the exact nature (timing and duration) of signaling interactions between the niche and HSC precursors and how these interactions contribute to determine cell fate choices (i.e., the production of HSCs by endothelial cells). Several laboratories have explored new possibilities to dissect the molecular and cellular components of the HSC niche by using a myriad of novel technologies. In their review, Weijts and colleagues discuss how these techniques have confirmed the complexity of the aortic niche and how the resulting data can be utilized to improve HSC production in laboratories.

Long road ahead

The evolution or development of new molecular approaches and the increasing power of so-called sequencing technologies to generate high throughput datasets using limited material are now readily accessible, relatively affordable and offer an array of possibilities. On the flip side, they also produce a huge pile of underexploited data. An important challenge ahead will be to manage and integrate all sequencing and spatial transcriptomic datasets in a comprehensive manner to obtain a global and realistic picture of what is happening in the aortic environment to promote HSC generation. This entails identifying the fine tuning of all HSC regulators and determining how they interact and/or interfere.

Functional validations and integration of transcriptomics (i.e. the study of RNA transcripts), proteomics (i.e. analysis of proteins), and epigenetic changes (i.e. modifications of the DNA that influence gene activity) in individual cells will be essential to fully understand how HSC production is promoted in vivo. This is in turn crucial to ultimately succeed in producing HSCs in vitro.

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