We don’t know the cause of death in these mice. In order to translate this technology to the clinic, we really have to understand the cause of this higher mortality… (Shinya Yamanaka)

It is actually not like we thought before - for me, this was the slogan of the conference of the year - the International Society for Stem Cell Research (ISSCR) in Philadelphia. Many previous hypotheses and journal reports were challenged. It’s understandable, because on the one hand, the field is new and dynamic, but on the other hand, a lot of publications come from many researchers’ desire to publish first and win the scientific competition. The cost of this race is too expansive: provocation in mass media and false expectations from desperate patients. Ok, let me tell you some of my thoughts about conference.

Organization:
was ok - not too bad but not so great either. There were some acoustic problems at the begining, and the absence of real food at the “final social mixer” turned me off. My main disappointment was about poster sessions - too short! 1.5-2h a day, 7pm security started to clear the hall of the scientific crowd. Nobody wanted to leave the posters. Secondly, I checked posters in the book (that summarized all the posters, presenters and locations) that i wanted to see and discuss about, ran there - and there was no presenter! Same with me - people can’t spend too much time near their own poster, because there are too many other posters to see (more then 1000) and too many people to speak with. This is a disadvantage and I have a solution - create an online database where I can search for any name or any topic and poster location easily instead of having to study this thick book. It’s so simple, why can’t the society do that on the web-site? And of course - another thing to do- extend poster session. Positive moment - free alcohol (which is definitely promote networking)!!! I was drunk every poster session.

Philadelphia near the Convention Center (I took this picture actually last year)

General trends:
1. iPS, iPS and iPS! It is a fetish!
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To get closer to the topic of discussion I’d like to give a short introduction.

It’s known that B-, T-, and NK cells arise from common lymphoid progenitor (CLP), while the rest blood cells (monocytes/macrophages, granulocytes, mast cells, dendritic cells, megakariocytes and erythrocytes) - arise from common lymphoid progenitor (CMP). Both CMP and CLP arise from one parent hematopoietic stem cell (HSC). This scheme (classical or canonical) was well-established in 1997-2000 by Irving Weissman lab and has been commonly accepted.

canonical scheme of hematopoietic tree:
(picture credit)

Let’s get close to the definition of “lineage commitment” through an example of T-cell development and CLP. For T-cell development, it was considered that CLPs migrate from the bone marrow to the thymus and give rise to mature T-cell types. This concept was recently challenged in the review by Avinash Bhandoola who reported that:

- several of the T-potent subsets in bone marrow and circulation in blood may contribute to the intrathymic pool;
- nearly all steps of commitment toward the T cell lineage, including the loss of myeloid, erythroid, and B potential, can occur extrathymically;
- many hematopoietic progenitors are capable of T lineage development if exposed to Notch signaling within an otherwise lymphopoietic environment;
- Unlike T- and B- potent Earliest Thymic Progenitor (ETPs) many others ETPs retain NK, DC and also demonstrate some myeloid potential.

Scheme of progenitor-successor relationships in T-cell development:
(legend)

These conclusions based on these latest findings indicate that a simplistic canonical hematopoietic division tree to the lymphoid and myeloid branches could be challenged. The last 2 papers, appeared in one of April’s issue of Nature, from USA and Japan show that a previously well-recognized distinction between two main hematopoietic branches — lymphoid and myeloid — needs to be reconsidered.

Today I’m interviewing Jerimah Bell - the first author of the paper: The earliest thymic progenitors for T cells possess myeloid lineage potential. Dr. Bell is the postdoctoral researcher in Avinash Bhandoola lab at University of Pennsylvania (USA).

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1. You show for the first time that Earliest Thymic Progenitors (ETPs), which reside in adult mouse thymus, possesses not only lymphoid but also myeloid potential. So, what kind of myeloid cells arise from ETPs and why does thymus need them? Is this process occur in the steady-state organ or is it created under special conditions?

JB: As we show in the paper, ETPs have the ability to generate granulocytes, macrophages, and dendritic cells, in addition to T cells, in culture. In vivo, we focused on the granulocytic potential of ETPs because granulocytes can be unambiguously identified as myeloid cells. In the accompanying paper in the same issue, Wada et al showed that macrophages also develop from early T cell progenitors in vivo. In addition, Ken Shortman has previously demonstrated dendritic cell potential from these progenitors in vivo.

The granulocytes that we observed appear to be present at steady-state, as they are readily detectable, albeit at very low frequency, in unmanipulated animals. We are currently investigating the necessity, if any, of thymic granulocytes. Our current speculation is that they may have some role in tolerance to granulocytic antigens.

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Hematopoietic stem cells (HSC) are able to self-renew and give rise to all the blood cell types. Almost all of self-renewing HSC are so-call long-term (LT-HSC), which are capable of reconstituting lethaly-irradiated mice for a long time, unlike short-term HSC, which keep mice alive for the first 2-3 months and give a lot of progenitors. Most LT-HSC are non- or very slow-dividing cells and reside within bone marrow niches in a dormant condition. The ability to maintain this non-dividing condition, or in other terms, stay in the G-0 phase of cell cycle, is called quiescence.

Scheme of cell cycle phases and place of quiescence:

Because it has been proposed that cancer stem cells (CSC) have the same qualities as normal stem cells, the vast majority of them also should stay quiescent and able to self-renew. Because majority of anti-cancer drugs target actively-dividing (cycling) cells, quiescent CSC stayed alive and caused relapses and progression of disease. It would be cool to target CSC precisely based on their unique qualities and eradicate cancer. Quiescence could be the new potential target for anticancer therapy.

Now, according to a recent international study, published online in Nature journal, we can get a solution for targeting quiescence of CSC.
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This picture shows one of the reasons why I was stuck in the lab for a couple of nights.
It’s a mouse liver and spleen - and together, they took up almost the whole abdominal cavity! The spleen was 12 times bigger than a normal one. You can see that the normal structure of liver was basically replaced by a lot of “tumor-like” nodes. So it seems that this animal died from cancer or metastasis.

But the magic is that I didn’t even inject any tumor cells or insert any oncogenes to cause these nodes, nor were they caused by parasites.
It happened when I just serially transplanted bone marrow cells in the 4th recipient from one of my genetically modified mice.
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We are always looking for the best way of searching for a job. It’s should be fast and effective.
RSS Feed technology is an incredible tool for it!
Here is manual how to use RSS for searching a job. As an example i took “stem cell research” field, but you can apply the same scenario for any life science disciplines.

1. Learn more (read and watch) about RSS feed
2. Install RSS-reader (I use Google Reader) on your computer
3. I recommend to use 4 databases for the search:
NatureJobs
type “stem cell” in search field –> search –> click “save this search as an RSS feed” –> copy this web address which will appear in your browser and paste in “add subscription” of your reader

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