Two weeks ago I attended (I even gave a talk) the annual meeting of the American Society of Hematology in San Francisco. It was not very productive for me, because most of my interests make it hard for me to focus and i drowned in the crowd of 20,000. So, mostly I was enjoying the city. But I picked some interesting reports and thoughts that I’m going to share with you here.
I’d like to focus on hematopoietic niche – how it’s affected with age and with malignancies and how can we play with niche in therapeutic settings?
First of all I’d like to summarize our knowledge about the aged hematopoietic system based on a few reports and studies that were done before.
In an aged organism, the hematopoietic system actually is very well balanced. The number of hematopoietic stem cells (HSC) is increased with age (5 fold more compared with young mice) but their function is declined. Thus repopulation activity is 2-3 fold less after transplantation of aged HSC. Also we can see a functional bias to myeloproliferation in an aged hematopoietic system, which is linked to increased probability of myeloid leukemias and declined immune function with age. So overall, an aged hematopoietic system doesn’t affect longevity.
Margaret Goodell‘s group (Baylor College of Medicine, Houston) compared gene expression profiles of aged and young HSCs and showed that many genes were up- (~1500) and downregulated (~1500). This gene profile showed dysregulation of many gene clusters rather than a few aging-specific genes. Also, aged HSCs showed extensive epigenetic changes. What they found was that many genes that were significantly dysregulated during HSCs were also dysregulated in other aged tissues. So, it seems like, on the gene level, HSC aging is not unique.
Amy Wagers‘s group (Joslin Diabetes Center, Harvard Medical School, Boston) studied the influence of the aged niche to HSC function. They showed that the HSC niche was altered with age and can be rejuvenated. She presented in vitro data that demonstrated the frequency of HSC cultured on niche cells from aged mice was 2 fold less than of those cultured on young niche cells. Furthermore, they performed a series of in vivo assays on parabiotic pairs of mice, which are surgically connected through blood vessels and have a common circulation system. They were able to rejuvenate aged HSC niches in old mice exposed (through common circulation) to “young blood” in parabiotic pairs as well as after short in vitro exposure (old HSC incubated on young nice cells). This experimental system allows to recover function of aged niches and subsequently partially correct HSC engraftment and lineage bias. Interestingly, Wager’s team got the same results with myogenic stem cells.
So the impact of these findings is that if we will be able to identify some rejuvenating factors circulating in the blood which make possible “niche regeneration” we can modulate stem cell function in the therapeutic settings.
Another exciting topic is the interaction between stem cells and their niches in cancerogenesis. It was proposed before that leukemic stem cell can compete with normal HSC for the niche. Seem like LSC have some mechanisms that allows them to win the competition and develop leukemia.
Yusuke Shiozawa from U of Michigan reported how a solid tumor can target HSC niche to establish metastatic footholds in the bone marrow. He used the prostate cancer model and showed that after tumor implantation and HSC transplantation without preconditioning, cancer and HSC colocalized in the endostel region of bone marrow and competed for the niche. They were able “play” with these metastases by decreasing (in osteoblasts knockout mice) or increasing (by parathyroid hormone administration) of niche component. Niche manipulation allowed them to increase or decrease metastasis in the bone marrow. Also they showed that after primary tumor removal metastasis can be mobilized from bone marrow to blood by G-CSF administration.
…these data provide the first evidence that the HSC niche serves as pre-metastatic niche for solid tumors…
Right after winning the competition for the niche, cancer cells start to modify it, making it suitable for themselves. Laura Calvi‘s group from U of Rochester reported about synergistic interactions between leukemic cells and osteoclast progenitors in bone microenvironment. No wonder that in altered leukemic niche we can see abnormal cells making bone marrow stroma and HSC microenvironment. Michael Andreeff from MD Anderson Cancer Center (Houston) shows that human mesenchymal stromal progenitor cells, derived from acute myelogenous leukemic bone marrow samples, have clonal genetic abnormalities. The same group presented another poster, demostrating the enchancement of chemotherapy-induced apoptosis of leukemic cells after disruption of leukemia/stroma interaction by CXCR4 receptor agonist. Based on these observations we can design new therapeutic drugs, which modify the stem cell niche and disrupt interaction between malignant cells and microenvironment.
What I was trying to tell you here is the significance of studying the stem cell niche. Look for upcoming publications for the details of these studies.