Extramedullary hematopoiesis and niche

by Alexey Bersenev on November 12, 2009 · 0 comments

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Existence of extramedullar (outside of bone marrow) hematopoietic stem cells (HSC) raises a number of interesting questions:

1. What is the biological role of extramedullar hematopoiesis?
2. Does it appear only in pathological conditions or does it also exist in normal steady-state organism?
3. How is it different from bone marrow hematopoiesis?
4. What is the intrinsic difference between marrow HSC and extramedullar HSC?
5. What is the origin of HSC in extramedullary sites? Do they migrate from bone marrow or just embryogenesis remnants?
6. What is the niche for extramedullar HSC?
7. Do osteoblasts and endosteal regions really matter for maintenance and normal function of HSC?

Few recent studies may shed a light on all of these questions. First of all I’d point to the Jinah Han study, which showed for the first time that adipose tissue is a novel extramedullary tissue with functional HSC.

The LSK population in the SVF was 0.004±0.001%, and 5×105 freshly isolated SVF cells gave rise to 13±4 multilineage colonies. Also, 0.15±0.03% of SVF cells was home to bone marrow (BM), especially near vascular and endosteal regions, 24 hours after blood transplantation. SVF transplantation was capable of generating a long-term (>16 weeks), but variable extent (2.1-32.1%) multilineage reconstitution in primary recipients, which was subsequently transferred to the secondary recipients by BM transplantation.

Recently I wrote about extramedullar hematopoiesis in the spleen. Whether HSC reside or circulate in the spleen under physiological conditions is still under disscusion. Given a relatively poor (compare to the spleen) circulation in adipose tissue, we can assume that HSC reside there. In particular, authors isolated HSC from stromal-vascular fraction of adipose tissue. Interestingly, the same fraction usually used for isolation of so-called “adipose-derived mesenchymal (stromal) stem/progenitor cells (MSC)”. These guys could be the only one I can think of which made a niche for adipose-derived HSC.

It was proposed that all MSC outside of bone marrow are actually pericytes – cells which are intimately connected to small blood vessell wall. So, the MSC are probably making the niche for HSC in extramedullary sites and vasculature is making the niche for MSC.

I wonder why most of the “hematopoietic community” is stuck with the so-called “osteoblastic niche“. I believe that this hypoxic environment could be the best for dormant HSC and preferred in homing, but it does not explain everything. We don’t have osteoblasts in the spleen and adipose tissue. More of that if you look at embryonic hematopoiesis – it occurs in multiple sites which have nothing to do with endosteum. Recently one more HSC niche was described – placental. What do you think all of these sites (spleen, placenta and adipose tissue) connects? Obviously not osteoblasts! Another question – can you define MSC and osteoblasts in bone marrow? They are sharing the same markers.

Another thing is models that are used to evaluate HSC niche. It is shown that only irradiation-based conditioning permits endosteal migration of HSC in trabecular bones. In non-irradiated recipients distribution of homed HSC is random.

Now, I’d like to talk a little about pathological conditions. The first observation: pathological extramedullar hematopoiesis can occur in multiple organs (described in skin, thorax, liver, kidney, dura mater, spleen, ureter, lymph nodes, ect. in conditions with myelofibrosis). So, something is making a pathological niche for displaced HSC in multiple organs and they do fine.

The second observation: HSC cold migrate to the extramedullary by ischaemic gradient. Recent work on the ischaemic kidney model evaluate the significance of SDF1-CXCR4 axis for this migration. Apparently, this migration axis is not a major player. Hierarchy of adhesion molecules, oxygen gradient, cellular environment and other factors are involved in HSC migration and determination of extramedullar hematopoietic site in pathological conditions.

Also I’d like to notice that MSC share many common homing/migration pathways with HSC in pathological conditions. I’d call them cells-satellites of HSC. Even simple irradiation significantly increases engraftment of both – HSC and MSC in bone marrow.

If we can connect and nicely shape all of these observations in one solid map, we will better understand biology of HSC. Knowledge of homing/migration signals will allow us to manipulate trafficking of transplanted cells and prevent dissemination of cancer cells.

also read: The true nature of the hematopoietic niche
The role of spleen in adult hematopoiesis
Searching for hematopoietic niche cells
Connotea tags: extramedullary /niche

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