When I was watching this lecture I was feeling so happy. Happy, because it was a story about the first cord blood transplantation in human and history of how whole field was established. Happy, because it was very personal, emotional and touching. Because the story was told by pioneer, the person who did the first cord blood transplant - Hal Broxmeyer. He is very enthusiastic and fascinating.

This lecture was given in 2007 on 49th Annual ASH meeting as esteemed E. Donnall Thomas Lecture and Prize.

(click picture to watch)

Even this lecture was recorded 3 years ago, I got to know so many things and most importantly - the history. I made a screenshot of this moment of the lecture because there are 3 heroes on the picture: Hangoc Giao, Hal Broxmeyer and Scott Cooper. In 1988 they took 2 liquid nitrogen tanks with cord blood samples and only through special connections with “PanAmerican” airlines moved them to Paris where Eliane Gluckman did the first transplant of cord blood. Very brave people!

I’d highly recommend you to watch this lecture.

I was fascinated by a recent talk given by Irwin Bernstein that I attended and a clinical study done by his group, which is exploring the possibilities of cord blood hematopoietic stem cell (HSC) expansion, published in Nature Medicine.

Authors were not only able to expand cord blood HSC drastically, but also performed phase I of clinical trial, which appear to be safe and preliminary data demonstrated earlier rapid myeloid engraftment in 10 patients.

HSC expansion - from lab to the clinic

If you follow the progress in the field you know that many HSC expansion protocols were published, but only a few of them attempted to enter to clinical trials. I suspect it happened because the vast majority of them didn’t pass all of validation tests, such as functional assessment of HSC function in xenotransplant models after ex vivo expansion. But some protocols entered into the clinical trials phase. Most of them were done on bone marrow or mobilized blood HSC, but some with cord blood (CB). Some trials didn’t move from phase I (safety and feasibility) to phase II (efficacy).

There is a huge demand for HSC expansion from cord blood particularly, because this is the main disadvantage for wide CB transplantation as an alternative to bone marrow and mobilized blood. Currently, a few CB HSC expansion protocols are undergoing clinical trials. But Bernstain’s study we can consider as more solid and successful at this point. Companies are also actively involved in developing CB HSC expansion protocols and supervise the clinical trials. For example, Fate Therapeutics licensed the “small molecule - HSC expander” from Children’s Hospital Boston and started a clinical trial.

Is it possible to keep expanded HSC in undifferentiated state?

Unfortunately, more likely the answer is NO. Even if you can detect the difference of expansion within long-term HSC subset by flow cytometry, these guys already primed to be actively dividing but not quiescent after the transplant. It could sound like a speculation, but nobody has proven the opposite so far. Almost all studies calculate HSC expansion difference based on CD34+ total expression or CD34+/CD38-. But even the last mentioned population does not represent HSC, because most of CD34+/CD38- are progenitors and you need to go way further (Lin-/CD34+/CD38-/CD45RA-/CD90+) in order to conclude something about long-term HSC. Most of the in vivo studies do not assess multilineage engraftent long enough to conclude confidently about superior repopulation of expanded HSC.

That’s why earlier trials didn’t show advantage in neutrophil and platelet recovery time - they expand something withing CD34+ total population, but not that we need.

Citation from the review:

Initial efforts to expand UCB progenitors ex vivo have resulted in expansion of mature rather than immature HSC, confounded by the inability to accurately and reliably measure long-term reconstituting cells. Ex vivo expansion of UCB HSC has failed to improve engraftment because of resulting defects that promote apoptosis, disrupt marrow homing and initiate cell cycling.

Double unit CB competition for engraftment

As you can notice from Bernstein’s study, they didn’t transplant just expanded CB sample but rather mixed with competing second - unmanipulated unit. For the phase I of clinical trial this sounds reasonable and safe. As we know, in double unit CB transplant only the one sample will win engraftment eventually, but another sample will act as a helper. In the case of this trial, expanded CB sample was a helper and unmanipulated CB unit was a winner. Why so? Because virtually all expanded CD34+/CD38- cells were multipotent and myeloid primed progenitors with very very few true HSC. Those very few expanded HSC, the authors were not able to detect a few months after transplant in 8 out of 10 patients. 2 patients with some signs of expanded long-term HSC engraftment were under observation for 240 and 180 days. But in one of them they were not able to detect signs of multilineage engraftment at the time point of 1 year and second patient didn’t possess engraftment in T-cells.

Numbers game

So, even though they transplanted 6 millions per kg of expanded CB CD34+ cells with only 0.24 millions (25 times less!) per kg unmanipulated CD34+, the second unit won engraftment in all 10 patients by 1 year of observation period. Why so?

2-7 millions per kg of CD34+ cells we need for clinically significant engraftment in adults. Magically, in pediatrics, 0.1-0.3 millions per kg of CD34+ CB cells is enough for sufficient blood lineage recovery. Average CB sample can provide the dosage only below 1 million per kg for adults. So we need to at least expand CD34+ cells twice to make the patients happy. Why are researchers shooting 50-150 fold expansion then? Because in reality almost none of long-term HSC expanded, but primed to progenitors in vitro, as I mentioned above. So, when we are talking about twice more expansion, we should achieve it naturally and proportionally in all HSC and progenitor subsets, without “cell culture artifacts”, such as “progenitors skewing”.

Do we really need HSC expansion for clinical success?

It seems like expansion of common myeloid (CMP) or multipotent progenitors (MPP) is good enough to achieve earlier and rapid neutrophil recovery. Maybe we even don’t need to chase robust expansion of long-term quiescent HSC in experiment and pre-clinical setup. I would not, just because if I see 30-100 times expansion of long-term HSC my “cancer caution” alarm starts beeping. Total number of CD34+ or CD34+/CD38- game could be efficient for good clinical outcome, as this study showed. I wonder what would happen if transplant was just expanded CB sample alone? No, better not to take such a risk, but keep mixing with unmanipulated unit.

Finding a Cure for Leukemia: A Stem Cell Story - documentary movie provided by Harvard Stem Cell institute.
This movie is very educational and recommended to watch!

In 2008 the Harvard Stem Cell Institute (HSCI) began working with Amy and E.W. Steptoe, local sibling filmmakers, who were in search of the next interesting topic for a documentary. Together we decided to tell the story of the effect that stem cell research is having now on the lives of leukemia patients and the challenges that lie ahead, both in fighting leukemia and in advancing stem cell research. This documentary was produced with the valuable input of HSCI Faculty members Scott Armstrong, MD, PhD, George Daley, MD, PhD, and Corey Cutler, MD; Toni Dubeau, RN, and Harvard graduate student, Sean Buchanan; and with the generous cooperation of Children’s Hospital Boston and the Joslin Diabetes Center.

(picture is clickable)

I’d like to share presentation that I made for journal club on paper: “mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells” published in Science Signaling 2 months ago. This is online version of presentation - without original figures.

The study give us more clue about how aging and stem cells are connected. Can we play with longevity through stem cells?

The current status of our knowledge I’d like to illustrate by quote from Sean Morrison’s review:

On the one hand, the changes in stem cell function that occur during aging would be expected to contribute to age-related morbidity by reducing tissue regenerative capacity. Moreover, the accumulation of genetic damage in stem cells likely contributes to increased cancer incidence during aging (Rossi et al. 2008, Sharpless & DePinho 2007). On the other hand, the effects of aging on fully differentiated cells are likely a major and independent contributor to age-related morbidity, cancer incidence, and degenerative disease. It remains unclear whether the changes that occur in stem cells are a major or minor contributor to age-related morbidity and life span.

You can find and download this presentation on Google Docs and Slideshare

How many lives could CB potentially save?

According to van Rood and Oudshoorn (2008), between 2000 and 2006, 151 000 patients qualified for an HLA unrelated donor transplant but, of these, only 64 720 actually received a transplant. [link]



Overall, 38% of patients for whom a search was started were actually transplanted. 28% of patients waited 6 months before failing the search procedure, 33% of patients were not transplanted despite a donor being found within 4 months, and finally, unrelated transplants were performed 2 months later than sibling transplants for the same indications. [link]

…timely CB access could benefit about one third of the patients requesting an unrelated donor. [link]

Public CB effectiveness

At a registry size of 10 million [bone marrow] donors, approximately 7 million additional donors are needed to increase the chance of matching by only 1%. [link]




…over 400,000 cord blood units donated and stored worldwide for unrelated use. Approximately, 14,000 unrelated cord blood transplants have been performed to date… [link]

… you can only donate your child’s cord blood if the baby is delivered in a hospital associated with a collection program. There are less than 200 collection centers in the US, mostly at large hospitals which deliver thousands of babies per year. [link]

The study showed that 50,000 donors would be required to provide at least one donor for 98% of the patients with at least a 4 out of 6 HLA match, to 80% with a 5 out of 6 match, and to 34% with a 6 out of 6 match. [link]

…estimate on the clinically useful size of a public CB bank to provide a suitable match for the UK population of 61 million people - 50 000 CB units. [link]

A non-biased bank of 50 000 would have around 15% of minority ethnic groups (about 7500 donors) and give a 36% chance of match for this group, and 80% for the whole population. If we bias collection towards the minority groups (i.e. doubling their representation to 30% of the inventory) the predicted figures are 74% for the whole population but 52% for the non-predominant ethnic groups. [link]

…the inventory should reach 150 000 donors to offer an 80% chance to the minority groups using the whole population… [link]

Private CB effectiveness

… about 900,000 cord blood units have been stored privately for personal use, with about 100 autologous transplants performed. [link]




Baseline assumptions included a cost of $3,620 for umbilical cord blood banking and storage for 20 years, a 0.04% chance of requiring an autologous stem cell transplant, a 0.07% chance of a sibling requiring an allogenic stem cell transplant, and a 50% reduction in risk of graft-versus-host disease if a sibling uses banked umbilical cord blood. [link]

Private cord blood banking is not cost-effective because it cost an additional $1,374,246 per life-year gained.

if the cost of umbilical cord blood banking is less than $262 or the likelihood of a child needing a stem cell transplant is greater than 1 in 110, private umbilical cord blood banking becomes cost-effective. [link]

None of the 93 US and Canadian physicians surveyed recommended private cord blood banking if there were no ill siblings and parents were of Northern European descent. [link]

There is no data on long-term viability of cord blood cells after 10-15 years. [link]

An analysis of 52 transplantation cases from cord blood units stored in private cord blood banks in the period 1994 to 2004 showed that of these 46 cases were actually allogeneic transplantation to siblings. Allogeneic transplantation is clearly the most common use of privately stored cord blood units. [link]

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Please discuss your thoughts in comments. I would like to join discussion.

Also read: Private cord blood banking - worth your money?