The whole point of efficient conditioning used in bone marrow transplant clinic is making “enough free niche spaces” for newly arrived donor stem cells or in other words - increase engraftment. Targeting selective surface markers or signaling pathways turning on in HSC will provide safe, non-toxic and efficient engraftment. The only thing that bothers me (and obviously not only me) is that pretty much the same approaches were proposed for efficient elemination of leukemia-initiating cells. Fresh example - targeting of STAT-5 signaling pathway.

This pathway is frequently activated in many leukemias and proposed to be a good “druggable target”. It happens that the same pathway is responsible for keeping normal HSC quiescent - some kind of “stemness-keeper”. So when we give an anti-STAT-5 drug to the patient we will kill his/her normal quiescent HSC, which are making all the blood in the body. We are really stuck with this problem. Virtually all selective anti-leukemic drugs are not really selective. Will they leave enough normal HSC to keep suffering patient survive? Will they kill all of leukemic stem cells with a guarantee of no relapse? Any ideas how to solve this puzzle?

I’d like to come back to conditioning now. Even if targeting of pathways is not going to work very nicely for leukemia, we can try to apply this technique for “making more niche available” in bone marrow transplantation. The first evidence for using inhibition of signaling pathways was recently demonstrated - good engraftment of donor’s HSC without irradiation-based conditioning. So, anti-STAT5 drugs can take the place in the line of “surface-targeting buddies” - cKit, MPL, CD45 ect. Can’t wait for clinical trials using this or similar approaches.

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Connotea tags: conditioning / STAT-5 / quiescence / c-kit / MPL / niche

I’m sad to announce that Nature Reports Stem Cells and the Niche will cease operations this week.

When we launched in June 2007, we wanted to see how Nature Publishing Group (NPG) could build online communities by providing original content freely available to all members of a fragmented community as well as the interested public. The topic could not have been better: stem cell research was then – and is still – expanding and exciting. It requires highly varied experts to think and work together. Unfortunately, the business of scientific publishing is more difficult than the choice of topic.

I’m truly sad about it. Yes business climate is currently tough, but what criteria was the NPG decision based on? Why NRSC? Apparently, it was good for business, and I didn’t understand the decision.

In the field of stem cell research we have very few sources of valid information with expert’s opinion and analytical points of view. Honestly, I knew only one source that was used science journalists - NRSC. It was. Now we don’t have any.

It was the source of educational information not only for the public, but also for the professionals working in the field of stem cells. For example, the Niche and NRSC was able rapidly get commentaries and clarifications of some controversial issues directly from the authors of papers, investigators, business executives or interview the experts. I, as some other blogging scientists, can not do this. Of course I can ask experts, but will probably not get a response. This is because I have no well known brand-name behind of me. I don’t represent Nature. Finally, NRSC integrated the public and the professionals into one community.

It’s very sad that we’re losing the reliable information sources in stem cell field. Not many professionals and no journalists are actually writing about it. I mean really analytical content with possibility of discussion, not just news or “copy-paste” blogs. We need volunteers, who can give valid information to the public and analytical information with discussions for professionals. Only this could spread the knowledge, prevent misleading information and fraud in developing therapies and commercialization.  Maybe it’s time for the community to take over scientific journalism and exchange high-quality information? We need enthusiasts for this initiative.

discussion on FriendFeed:

I’ll share this poll on Twitter, FriendFeed and LinkedIn.

Please take your time and vote. Please call your friends and colleagues to participate. You should be involve in stem cell research.
You can choose 1 or 2 options when voting.

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you can link, share, tweet, embed this poll and leave your comment

Some rare reports suspected mother-to-fetus cancer transmission in cases of leukemia and melanoma, but all of them were lacking genetic evidences for a shared materno-fetal malignant clone. Now we got it. 28-yo mother died from uncontrollable bleeding caused by leukemia in about a month after delivery. An infant was diagnosed with leukemia caused by the maternal clone of cancer cells 11 months later.

Placenta plays an important role in immuno-surveillance and can selectively regulate trafficking of cells between mother and fetus. The authors detected HLA deletion on the transmitted cancer cell clone, which provided immunological invisability of leukemia in the fetus.

So, what about fetal cells in mother’s body? This topic is full of controversial reports and uncertainties. First of all I focused on cancer and got the following:

Although their function is not yet known, evidence in skin, breast and thyroid cancer favors the involvement of these fetal cells in repair mechanisms rather than a role as cancer stem cells in cancer propagation.

So, fetal cells actually protect the mother from some kind of cancers. Awesome! Nevertheless, one of the theories proposed that fetal stem/progenitor cells can act as a cancer stem cells, facilitating cancer progression.

Also, I was thrilled by the investigation that baby’s hematopoietic stem cells could be isolated from mother’s blood as long as a year after the baby’s birth. In the first few months after pregnancy hematopoietic progenitors circulate in relatively high concentration - 1-2 cells/ per 1 ml of maternal blood. How cool would it be if someone could develop the technology of isolating and expanding them in case of autologous transplant in case the baby gets a hematological disorder but cord blood was not collected.

Another interesting thing that I discovered in the review is tissue repair magic:

Fetal–maternal microchimerism is associated with tissue repair. It is important to define the possible role of microchimerism in normal organogenesis and determine how cellular aging affects the repair functions of maternal and fetal microchimeric cells.

I’d encourage you to read this review. You will get to know what kind of cells can migrate, how we can detect them, association of fetal cells with autoimmune diseases, cancer, tissue repair and clinical applications of these knowledge.

… clinical ramifications of fetal–maternal microchimerism for stem cell transplantation and therapy, organ repair and cancer therapy are only just beginning to be studied and understood, but represent an exciting new research field and raise fundamental questions about the biological consequences of microchimerism.

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picture:
The human foetus at about four months (17-18 weeks) showing the head & upper limbs & the umbilical cord which connects the foetus (at the navel) to the placenta…
Credit: EDELMANN / SCIENCE PHOTO LIBRARY

The recent report summarizes all of the autologous HSCT for autoimmune diseases (AD) treatment performed in Europe during 12-years period.

This observational study (1996-2007) analysed all first AHSCT for AD reported to the European Group for Blood and Marrow Transplants (EBMT) registry. Primary end-points were overall survival (OS), progression-free survival (PFS) and the 100 days transplant related mortality (TRM).

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The transplant activity in Europe by disease and years is shown this table:

MS - multiple sclerosis; SSc - systemic sclerosis; RA - rheumatoid arthritis; SLE - systemic lupus erhytematosis; JIA - juvenile idiophatic arthritis; HIC - hematological immune cytopenia
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I picked one of the most important outcome characteristics, analyzed in the article - 5-years progression-free survival to illustrate efficacy of therapy.

5-years progression-free survival (PFS):

The aim of this paper was to merge the longer term follow-up of the 473 patients previously reported by the EBMT in 2003 with the cases reported to the Registry thereafter, in order to analyse the determinants of the clinical responses in 900 severe ADs patients treated by a first autologous HSCT, which is the largest number analysed worldwide so far. Our data confirm that autologous HSCT is a valid therapeutic option for patients with an AD progressing despite standard therapy.

It was no comparison of HSCT outcome with the “standard - non-transplant treatment”, but most enrolled patients were resistant to previous (standard) therapy, especially in multiple sclerosis trials.

For more details I encourage you to read a full report. It’s an open access paper.

These results sum up ten years of an EBMT-EULAR international collaborative network and form the basis for future directions in the field. They strongly support the ongoing European and North American phase III trials in severe ADs, aimed to compare autologous HSCT with standard therapies in SSc (namely, the ASTIS trial (www.astistrial.com) in Europe and the SCOT trial (www.sclerodermatrial.org) in North-America), MS (ASTIMS, www.astims.org), Crohn’s disease (ASTIC, astic@nottingham.ac.uk) and SLE (ASTIL).

It was interesting for me also to look at this EBMT report, which summarizes allogeneic HSCT for treatment of autoimmune diseases, which came up earlier this year.

Thirty-five patients receiving 38 allogeneic transplantations for various hematological and non-hematological AD were identified. Four patients had had an allogeneic HSCT for a conventional hematological indication in the past. Fifty-five per cent of the transplantation procedures led to a complete clinical response of the refractory AD and 23% to at least a partial response. The median duration of response at the last follow-up was 70.7 (15.2–130) months. Three patients relapsed at a median of 12.3 months after HSCT. Treatment-related mortality at 2 years was 22.1% (95% CI: 7.3–36.9%). Two deaths were caused by progression of AD. The probability of survival at 2 years was 70%. No single factor predicting the outcome could be identified. The retrospective nature of this study and the heterogeneous, partly incomplete data are its limitations. However, allogeneic HSCT can induce remission in patients suffering from refractory AD. These data provide the basis for carefully conducted prospective trials.

So even allogeneic transplant gave 75% of positive response. The authors conclude that results are encouraging and trials should be completed. Allogeneic transplant could be an option for some selective patients who are not suitable or previously underwent autologous HSCT.

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Connotea tags: clinical trial, autoimmune, HSC transplantation

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Table and quotes from the original paper used with permission of publisher. Copyright “Ferrata Storti Foundation”, Pavia, Italy.

The Stem Cell Review is a 10-part series on the science, medical applications, and business of stem cells. This program will give you a clear and concise understanding of the state of stem cells today, with the additional depth and expertise you would come to expect from the most renown authorities in the field. The Stem Cell Review is a BioBusiness.TV Original Production presented by Bill Kridel.

So far 2 episodes were aired since October 1:
Episode 1: Stem Cells at a Glance
Episode 2: Allogeneic or Autologous?
stay tuned!

This is high quality content. Recommended to watch!

… after 45 years, we have been unable to place the general notion of ’stemness’ on a purely molecular footing. Of course, the fact that a goal has not been achieved after a long time does not mean that the answer in not around the corner. But it does give one cause to wonder whether something we are doing needs to change, either the question we are asking or the way we are approaching it.

In an online interview for “The Scientist” journal, Dr. Lander pointed out that current status of the stem cell concept is misguided.

We want to nail down the concept, but we need to nail it down in a different way. So if this is really a network property — that is, a property at a higher level than the cell itself — then nailing down the concept means knowing something about molecular properties of the cell and molecular properties of cell types it produces, the molecular properties of things that they produce that then feed back on the stem cells? It’s a system level property, so we need to have information about a whole system.

I shared discussion on FriendFeed and started to comment:

Then James Till commented in paper’s discussion section. Also he posted on the Cancer Stem Cell News blog.

If we come back to the article, we can see that Dr. Lander doesn’t actually argue the existence of stem cells per se, but offers an alternative way to explain how this system functions:

The jury is still out on whether all self-maintaining tissues exploit stochastic renewal with feedback or whether some, do in fact rely on invariant asymmetric stem cell divisions.

…the fact that stem cells very often do divide asymmetrically in no way implies that asymmetric division is the mechanism of tissue homeostasis. One can achieve homeostasis through feedback control, and still expect to see frequent (albeit not obligatory) asymmetric division, especially in tissues with rapid turnover in which stem cells must divide many times during the lifetime of the organism.

So the discussion turned into an assessment of our way to study and explain stem cell functions and characteristics - “stochastic model with feedback control” versus “asymmetrically dividing defining stem cell population” withing a given tissue. You can find a more detailed explanation of stochastic model of renewing withing the lineage in Lander’s recent article.

The final point of the article that was made:

In summary, it would seem that the concept of stem cell indeed has the potential to hold us back - especially if we focus on demanding from it things it cannot give. But if we can re-fashion our thinking at a different level - in which systems relationships and dynamics take the place of molecular signatures and simple gene regulatory circuits - then there is a chance that the concept of stem cell will continue to light the path toward biological understanding.

I don’t think that stem cell concept is “holding back biology”. I think it’s evolved. I’d agree with Dr. Lander that it’s a “natural course of science” and current findings and discussions like this will guide us in the way of approaching the problem in the future.

I disagree that most of stem cell biologists are “stuck in searching molecular signature of stemness”. I’m a stem cell researcher and don’t care much about it. The field is so broad. The system approach of studying adult stem cell was very well known and established. We know that stem cell lives in populations dependent on environmental cues (niches). We knew that there is a heterogeneity within the population and frequently pure stem cell can not represent the whole population.

I’m so glad that during the last week this discussion was so productive and useful for me. It was broadcast-ed, blogged, twittered, shared, interviewed, podcasted and commented in open science manner. It is a great example how scientific discussion should be done online!

Irving Weissman - Professor of Pathology and Developmental Biology at Stanford University and Director of the Stanford Comprehensive Cancer Center and Stanford Institute for Stem Cell Biology and Regenerative Medicine.

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also read:
How to train the immune system to kill cancer stem cells?
Cancer stem cells - how mouse model can change the concept Complexity of cancer stem cells
Validity of the cancer stem cell concept under discussion

also watch:
Sean Morrison - Stem cell and cancer
Robert Weinberg - Cancer stem cells and malignant progression
Catriona Jamieson - The molecular evolution of leukemic stem cells
Irving Weissman - Stem Cells: Units in Regeneration, Cancer, and Natural Selection

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Connotea tags: cancer stem cell, CD47, Weissman IL

Unless we resolve this, it will have a tremendous negative impact on stem-cell research.
Warren Olanow

I was inspired by a recent commentary on safety matters of translational neurotransplantation written by Evan Snyder - neurobiologist from Burnham Institute. I’ll get to it at the end.

Transplantation of fetal cells to repair non-functional neuronal tissue is only one field of cell therapy where we can trace long-term (5-15 years) outcome. That’s because clinical cellular neurotransplantation started to get explored as early as 20 years ago. The rational was quite simple - replace damaged brain tissue by the same functional tissue taken from an aborted fetus.

I’ll try to summarize only some histological findings of individuals who underwent clinical neurotransplantation and eventually died from different reasons. I’d like to focus on fetal graft pathological findings that were discovered many years (7-15) after transplantation. There are a number of reports that indicate short-term morphology and function of fetal neurograft is actually good, which is usually associated with positive clinical outcome. One of the best studies was done on Parkinson’s Disease (PD) patients and published in 2001. Now, let’s look at some interesting published cases.

The first? bizarre case in 1996 - PD patient got transplant in China

the case:

We report the case of a 52-year-old man, who, 23 months earlier, received both intrastriatal implantation and intraventricular infusion of tissues derived from fetuses of 15 to 16 weeks and 5 to 6 weeks gestational age. Clinical improvement, as measured by increased amounts of “on” time with reduced levodopa requirements, seemed to occur over the subsequent months. He died suddenly at home after a several-hours interval of progressive lethargy and breathing difficulties.

autopsy findings:

At autopsy, the diagnosis of PD was confirmed. Intrastriatal graft sites were identified, but contained no viable neurons; astrogliosis, focal microgliosis, and mixed inflammatory response, suggesting allograft rejection, were present. Surprisingly, the intraventricular tissues survived and showed ectodermal and mesenchymal, but no neural, differentiation, as well as cellular response; the left lateral and fourth ventricles were filled completely by this proliferated tissue.

Parkinson’s Disease affected grafts

Three postmortem studies published in Nature Medicine in 2008 examined long-term fetal transplants results. You can read studies here, here and here. I’ll just cite a commentary:

… three independent laboratories report their autopsy-controlled findings in a total of eight subjects after such surgery.The long-term clinical benefits in six individuals who survived 9–16 years after surgery proved to be limited, and three of them showed brain pathology typical of Parkinson’s disease at autopsy—alpha-synuclein inclusions (Lewy pathology).

…The findings—such as the development of parkinsonian pathology in some transplanted neurons—underscore the limitations of this approach.

Huntington’s Disease (HD) - graft degeneration in 10 years

the case:

Two of 3 patients with HD reported here, who underwent neural transplantation containing striatal anlagen in the striatum a decade earlier, have demonstrated marginal and transient clinical benefits.

autopsy findings:

Here we report in patients with HD that (i) graft survival is attenuated long-term; (ii) grafts undergo disease-like neuronal degeneration with a preferential loss of projection neurons in comparison to interneurons; (iii) immunologically unrelated cells degenerate more rapidly than the patient’s neurons, particularly the projection neuron subtype…

Israeli boy case - the first?? report of a human brain tumor complicating neural stem cell therapy

To remind you about this scandalous clinical case I refer you to my earlier post - Potential risk of tumor formation from adult stem cell therapy could be underestimated.

A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm.

Why was it a scandal? Because news media have taught that “stem cell therapy caused tumor formation”. Sounds like a horrible impeachment of the whole cell therapy field. Ridiculous! But a few days ago I was so happy to see an independent investigation of this case by the experts:

Our review of their data, together with unpublished studies performed contemporaneously on similar material from the same Moscow institution, argue that the report is inaccurate: the cells implanted were not NSCs (Neural Stem Cells).
Furthermore, the histopathologic picture of the cellular accumulation is not one of neoplasia. Neoplasia, too, has a rigorous definition with archetypal features that were unfulfilled by the photomicrographs shown in the study.

Taken together, the findings from the two cases suggest that an unselected, unfractionated
whole fetal forebrain homogenate, not an NSC infusion, was administered—in inappropriate doses, in inappropriate locations, by an inappropriate route and for inappropriate cell replacement indications. In both instances, an unfortunate neurologic condition was worsened, and the suffering of the children was exacerbated.

Some lessons to learn

1. Fetal neural tissue transplantation for replacement of affected non-functional host brain probably have only short-term clinical effect in some conditions (PD, HD) in some patients and linked to graft survival.
2. Long-term outcome and morphological findings raises a question about future of this therapeutic approach. It’s like a long-playing pill - give some symptoms release in some patients for 1-3, maybe 5 years and then… But would you get a new pill like that in your brain?
3. All of these transplant cases (or most of them) were done not under government regulation and didn’t use “defined cell product”. This is a difference from modern trials, so we can’t extrapolate.
4. None of these cases described that “stem cells” were injected. Seem like none of them describe tumor formation, but some unclear cell proliferation (Chinese and Moscow’s cases).
5. Wrong interpretation of these findings by mass media and absence of independent expertise could lead to unfortunate cell therapy field discredit.

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picture credit: GEOFF TOMPKINSON / SCIENCE PHOTO LIBRARY