Amazing stuff!
"A single molecular switch is essential for blood stem cells to enter an activated, regenerative state in which they produce new blood cells ... The discovery could lead to more effective bone marrow transplants and gene therapies. ...
The researchers ... found that a DNA transcription-regulating protein called FLI-1 has a critical role in this regenerative process for blood stem cells, which are mostly resident in the bone marrow until they are stimulated or “mobilized” to move into the bloodstream. They showed that transiently producing FLI-1 in quiescent adult mobilized bone marrow stem cells activates them so that they swiftly expand their numbers and have a better chance of being transplanted successfully into a new host. ...
In the study, the researchers used single-cell profiling and other techniques to analyze differences in gene activity between quiescent and activated blood stem cells. Eventually they zeroed in on FLI-1, a transcription factor protein that can control the activity of thousands of genes. Its absence, they showed, keeps blood stem cells quiescent, and largely shuts down these cells’ interactions with surrounding marrow cells, in particular the specialized endothelial cells that compose the blood vessels.
FLI-1’s activity, in contrast, restores stem cells’ connections and co-adaptability with their microenvironmental endothelial cell niche, also known as the vascular niche. FLI-1 pushes them into an activated, regenerative state – greatly improving their ability to expand and restore the blood cell supply in a new host.
The mutations that drive overactivity of FLI-1 are known drivers of some leukemias. However, the researchers developed a method for stimulating blood stem cells with FLI-1 for only a few days at a time, using an approach similar to that of modified mRNA-based vaccines. ..."
From the abstract:
"Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined.
Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation.
Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine."
Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing (no public access)
Who knew blood could be so beautiful! A colorized image of adult mobilized blood stem cells (small and roundish) into which Fli-1 modified mRNA has been introduced, expanding on top of engineered vascular endothelial cells.
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