Why do we need to know the relationships among hematopoietic stem cells (HSC) and cell types surrounding them in bone marrow? The general issue is whether the surrounding cells really matter in order to maintain HSC self-renewal ability (“stemness”).
I want to remind you that search for niches has led to the identification of a few cell types in bone marrow which are important for HSC maintenance – osteoblasts (endosteal region), endothelial cells (vascular niche), adipocytes and mesenchymal stromal cells. However, the field is still full of controversies and unsolved questions:
– how do niche cells interact with each other and which one is important? Cell-cell contact or just signaling (receptor-ligand interaction independent from cell type) or both?
– are there multiple niches (endosteal and vascular at least) or it’s just one?
– what signaling is play an important role?
One of the important reasons why controversies began (IMHO) is that different research groups used different set of markers for HSC, different techniques and models. They even study different bones (some calvarial, some – long). So to me it’s obvious that people are getting different results.
Series of recent Nature papers from “pioneers in the field”, gave us a hope to solve some of these questions. Both – David Scadden‘s and Linheng Li‘s groups used sophisticated visualization techniques to keep track of HSC homing, their site of lodging and following behavior. David Scadden’s technique allows us to visualize labeled HSC in live animals for the first time!
I was really happy to find that conclusions from both studies complement each other. They showed that only in irradiated mice HSC tend to home and stay in endosteal region, which is highly vascularized. This confirms a previous study performed by Von Andrian’s group in 2002. In contrast, progenitors or HSCs transplanted in steady-state host distribute randomly and more in central marrow. But the most important conclusion:
The data presented here demonstrate that the previously proposed dichotomy between distinct osteoblast and perivascular niches is not anatomically feasible in the calvarium: osteoblasts are perivascular. We cannot exclude perivascular-only niches within the diaphysis of long bones or in non-bony tissues such as spleen; however, the microarchitecture of trabeculae indicates a joint periendosteal–perivascular niche.
The second study confirmed that this is also true for long trabecular bones. So seem like now we have one niche with endosteum – this site doesn’t exclude vascular component and influences. But even Scadden’s group indicated that cells with different phenotype localized differently, I didn’t find in the paper their results after transplantation of “Morrison’s HSC” (=SLAM) – where do they go? According their poster on ISSCR’08 SLAM HSCs lodge closer to central marrow!
It seems that visualization studies allow us better localize HSC in bone morrow, compared with previous immunohistochemical techniques, but it was done in homing condition – after transplantation. So, we still not sure what’s going on in situ with resident HSC in bone marrow.
Yet another controversial question we got from the Li’s and Morisson’s studies. Li’s visualization study showed that HSC homed in endosteal region stick to N-cadherin+ osteaoblastic cells, but some of them interact in central marrow and some don’t interact at all. More confusions added recent Sean Morrison’s report, says something like “HSC really do not care about N-cadherin signaling”. What do they care then? Yes – not 1 or 2 particular type of niche cells and not some particular signaling pathways – should be many and interaction is more complex.
Irving Weissman’s group decide to simplify this complexity and dissected one particular cell population from fetal bone tissue, which is able to make functional bone with marrow and host HSC in ectopic site. Here I’d like to indicate that in 1982 russian scientist Alexander Friedenstein published results of his experiments “marrow microenvironment transfer by heterotopic transplantation of freshly isolated and cultured cells in porous sponges”. Basically, by transferring of mesenchymal stromal progenitors he got ectopic “hematopoietic organ” with bone and marrow according histological findings.
More then 25 years after, Weissman replaced sponges to “Matrigel”, picked fetal bone as potential source on niche cells and added in this story the main component – flow cytometry! CD105+/Thy1- at least bipotential (chondro- and osteo) cells from fetal bone able to reproduce full “hematopoietic organ” with migrated and functional (!) host HSC. The process call “enchondral ossification” and could be provided only CD105+/Thy1- cell population with following host vascularization and marrow formation.
Now it seems like Weissman came back to “Friedenstein cells” – mesenchymal stromal progenitors and “added a new letter in the story”. But even so, СD105+/Thy1- can not make “functional niche” themselves, they just initiate the process and to complete it they need osteoblasts and vascular cells.
I’d remind you that СD105+/Thy1- is not the first “hematopoietic niche cell” candidate. CD45-/Ter119-/OPN+ (osteoblastic) were used in vitro as a niche candidates by Amy Wagers group. More of that, Paolo Bianco’s group also repeated Friedenstain’s experiments, but with yet another cell population – MCAM/CD146+ human (!) subendothelial cells appeared to make both bone and marrow in immunodeficient mice.
I can’t wait for continuing intriguing “searching for hematopoietic niche” detective series!