More insight into steady state hematopoiesis

by Alexey Bersenev on February 21, 2015 · 0 comments

in hematopoietic

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Lat year, I’ve written about new methodology for tracking steady unperturbed hematopoiesis in situ. Recently, one more method, involved genetic labeling, was describe by group of German authors. New methodologies for studying steady normal hematopoiesis will allow us to make an important step from highly artificial bone marrow transplantation to more natural and precise models. Even though transplantation models is still a “gold standard” for assessment of hematopoeitic stem cell (HSC) function, everybody in the field would acknowledge of its disadvantages – myeloablation by irradiation (which makes animals very sick), extensive cell manipulation ex vivo and delivery of HSCs in highly toxic environment. New genetic tracking methods may unveil many differences with conventional HSC transplantation models in terms of data interpretation and change our understanding of hematopoiesis and HSCs behavior.

Katrin Busch and co-authors, used Tie2 marker to genetically label mouse HSCs in inducible system. Tamoxifen induced the system and allowed a “chase period” – tracking the fate and frequency of HSCs in steady state mice. It turns out that active contribution of HSC in normal hematopoiesis was about 100 times higher than in transplantation models. It was mostly because of polyclonal repopulation from so-calleld short-term HSCs, but not from long-term HSCs. The use of transplantation model as a control demonstrated high variability of long-term HSC contribution and frequent “loss of HSC clones”. So, unlike in situ labeling, transplantation model suggests oligoclonal HSC-derived hematopoiesis. The authors also demonstrated that long-term HSC are activated by “toxic stress factors” and during embryogenesis.

Some interesting calculations from the study:

… a mouse has ~17,000 HSCs; 30% active HSCs indicates that ~5,000 HSCs contributed to normal haematopoiesis within the observation period.

On average, per day, 1 out of 110 HSCs differentiates into an ST-HSC, and 1 out of 22 ST-HSCs differentiates into an MPP…

Important conclusions:

Inducible labelling of HSCs in normal mouse bone marrow showed that during development HSCs are rapidly used to establish the haematopoietic system. Once this is accomplished, individual HSCs are only rarely active, but over time a large portion of HSCs contributes to adult haematopoiesis.

The observed HSC oligoclonality is hence a hallmark of post-transplantation but not normal unperturbed haematopoiesis. These findings indicate that experimental and possibly also clinical HSC transplantations are based on a much smaller stem cell foundation than physiological haematopoiesis.

…true HSC deficiency may go unnoticed for extended periods of time while functionally impaired ST-HSC and MPP compartments would cause rapid signs of acute bone marrow failure.

I’m always curious about potential impact of a drug in inducible genetic models. The authors did not discuss it, but at least one recent study indicates profound impact of tamoxifen on HSC subsets.

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