Stem cell fitness, competition for bone marrow niche and leukemia

by Alexey Bersenev on May 17, 2010 · 0 comments

in niche

 
We can compare organization of cell compartments in our body with a wild world of nature where each creature is a single cell. They communicate, create communities (tissues and organs), fight with enemies (bacterial invasion and immunity), reproduce (divide) and compete for the best microenvironment or niche in order to survive. I believe that cells in our body follow the universal laws of nature and should undergo natural selection upon competition. One of the best examples of this model could be the competition of hematopoietic stem cells (HSC) for niches in bone marrow.

Cell competition in stem cell compartment as a mechanism of normal tissues turnover was investigated over the past decade in some model organisms. We don’t know exactly how stem cells compete for the niche in mammals, but we know that this process should exist in order to eliminate errors and damages and keep us healthy. Recent work by Bondar and Medzhitov and by Marusyk et al. can give us more insight into mechanisms of stem cell fitness and competition for the niche.

Both groups showed that loss of tumor-suppressor gene p53 gave HSC competitive advantage for engraftment and niche occupancy upon stress conditions (irradiation). Gain or loss of competitive fitness depends on relative level of p53, presence of competitors and damage factor (irradiation). Importantly under normal conditions p53 is dedicated to repair DNA damage and insure that healthiest (fittest) circulating HSC occupy a vacant niche. In this case p53 deficiency appears to be selectively neutral.

Douglas Green in his excellent commentary, besides labeling cells “winners” or “losers” introduced new guys – “cheaters”. Cheaters carry a mutation which could lead to loss of tumor-suppressors level. These guys, unless eliminated by resistance mechanisms, eventually become winners, dominate a niche occupancy and initiate neoplasia.

So on one hand, loss of tumor-suppressor protect HSC from irradiation and give them “cellular mojo” – power to win competition for the niche and sustain hematopoiesis, on other hand this hematopoiesis could not be normal anymore. Selection for winners with low level or mutated tumor-suppressors will always lead to clonal expansion and domination (clonal evolution). These cells more definitely will be prone to acquisition of additional mutations and responsible for neoplastic process initiation. It is very reminiscent of the phenomenon of hijacking bone marrow niches by leukemic cells or disseminating metastatic cells from solid tumors. It also reminds me of a phenomenon of cancer stem cell resistance to irradiation. It is less likely that loss or mutation of p53 is the first hit, but it gives us some clue how abnormal cells can compete for niches and dominate the healthy cells under stress- or carcinogeneic conditions.

It is well known that genes – tumor-suppressors – also negatively regulate stem cell self-renewal. Complementary to this notion, Bondar showed that stress-induces p53-medicated competition occurs in long-term HSC. I’d like to speculate that highly quiescent or dormant HSC could be the first target for this selection upon mutation. As you may know, a few recent studies demonstrates dramatic increase of reprogramming efficiency of iPS cells upon deletion of tumor-suppressors. So tumor-suppressor deficiency makes cells “super-stem” or in other – sad words – initiate carcinogenesis. The analog of these kind of “super-stem” cell in hematopoietic system is dormant HSC. I wonder if “high degree of stemness” made them more susceptible to mutations in comparison to active (primed) HSC.

To me, most importantly, this work provided evidence for carcinogenesis (irradiation)- induced selection. It contradicts the assumption that oncogenic mutation alone caused by carcinogenic factor can initiate the malignant process (mutagenesis versus selection). It is also important that this selection occurs in context of stem cell niche and can give us a clue of how neoplastic process is initiated and progresses.

Darwin imagined, in his last paragraph of the Origin of Species, a tangled bank of competing organisms, and it now seems that we can stretch his analogy to the dynamic interactions of cells that populate niches during development and repair.

***********
citation: Douglas Green

{ 0 comments… add one now }

Leave a Comment

Previous post:

Next post: