Cord blood transplantation research
Nudging transplanted cord blood stem cells in the right direction

bone marrow transplant cord blood stem cells 

Bone marrow of a patient 30 days after a cord blood transplant, with donor-driven hematopoiesis (blood cell formation) taking place. 

If you require a peripheral blood or bone marrow transplant but lack a matching donor, cord blood could prove especially useful. Leukemia and lymphoma patients are among the main beneficiaries of cord blood transplants, alongside those with other blood disorders.

As its name suggests, cord blood is found in the placenta and the attached umbilical cord after childbirth. It’s a rich source of stem cells (CBSCs), but because these are limited in number and may not be enough for effective transplants in adults, much effort has been devoted to expanding CBSCs in vitro. Additionally, guiding infused CBSCs to their final destination – the bone marrow – and keeping them from circulating to other tissues is no straightforward task. This “homing” process is necessary to jump-start CBSC engraftment, during which they repopulate the bone marrow and produce normal blood cells. When not handling a busy schedule of patients, Omar Aljitawi, M.D., of Cancer Biology, is investing considerable time at the bench figuring out cord blood transplantation’s underlying biology. 

Where an efficient expansion method for CBSCs is concerned, Aljitawi has found that by first seeding scaffolding material with stromal cells isolated from Wharton’s jelly – a gelatinous substance within the umbilical cord – then coaxing them into becoming bone-producing cells, an artificial bone environment results in which CBSCs readily proliferate. This approach needs to be refined, however, so CBSCs grown in the laboratory maintain their “stemness” rather than differentiate into other cell types. And because much of the research field in cord blood transplantation is currently focused on the issue of expanding CBSCs, Aljitawi has opted to skew his own bench work in favor of the second problem: getting these stem cells to home to the bone marrow upon infusion.

Newborn babies have high concentrations of circulating CBSCs that decrease over time as the cells reach the bone marrow. Along with this initial spike in stem cell numbers, a newborn’s blood has high oxygen levels and low amounts of the hormone erythropoietin. Aljitawi began his research with the theory that increased blood oxygen – a certainty as newborn lungs fill with their first cries – accompanied by a corresponding drop in erythropoietin somehow trigger the bone marrow homing signal for CBSCs. 

Next, he began investigating ways to lower erythropoietin levels in the blood and hit on hyperbaric oxygen (HBO) therapy – the medical use of oxygen at a level higher than atmospheric pressure – as one possibility to test his hypothesis. Undeterred by his lack of experience in designing the necessary animal studies, Aljitawi sought the help of several collaborators, including George Vielhauer, Ph.D., who brought him up to speed on establishing proof-of-concept in mice, and Jeff Radel, Ph.D., who assisted him in turning an unused autoclave into a convenient – and cheap – animal-sized hyperbaric chamber. The group recently published their findings in Blood Cells, Molecules and Diseases, reporting that HBO therapy does improve the grafting of infused CBSCs in mice. 

Aljitawi has since started a pilot study in the clinic, with two patients accrued to date. “It’s not a phase I trial because HBO therapy is in fact medically safe,” he says. “But in this particular setting, our subjects are already dealing with a host of unpleasant side effects from chemotherapy and radiation, so we have to be sure this additional treatment won’t further complicate matters.” 

Chronic chemotherapy-induced nausea, for instance, could prove something of a bugbear, because patients on this study need to spend two hours in a hyperbaric chamber prior to receiving their cord blood transplant. Aljitawi is cautiously optimistic on this count, however, given that neither of his two patients experienced such difficulties while undergoing HBO therapy, despite expectations to the contrary. Both also recovered well from the transplant procedure, and preliminary evidence indicates that HBO therapy may aid CBSC engraftment in a clinical setting. Encouraged by these results, Aljitawi is now extending this therapy’s application to other types of peripheral blood transplants, most recently the autologous (self) variety. 

“Chemotherapy drugs result in injured tissues releasing a whole host of biological factors that could act negatively on freshly-infused stem cells, even wipe them out,” Aljitawi says. “It’s called a cytokine storm, and the body just isn’t very receptive to newcomers. But we think HBO is somehow able to dial things down, at least temporarily, giving the stem cells an opportunity to reach the bone marrow.”

So apart from possibly coordinating with erythopoietin to direct CBSCs toward the bone marrow, it may be that increased levels of oxygen in the blood are a positive influence on the homing process simply by improving the stem cells’ chance of survival in a hostile environment.

“It happens early on – within hours to the first few days of infusion – and is very transient,” Aljitawi says of CBSCs heading to the bone marrow, “which is why understanding all we can of this critical window, especially the molecular mechanisms involved, is pretty important. Then we’ll be better positioned to optimize therapies like HBO for cord blood transplantations.”

Funding sources for this research

  • The Robert K. Dempski Cord Blood Research Fund
  • Frontiers Pilot and Collaborative Studies Award: “Hyperbaric oxygen to improve engraftment post-cord blood transplantation”
  • Southwest Oncology Group (SWOG)/Hope Foundation Translational Research Award: “Pilot study exploring the use of hyperbaric oxygen in autologous PBSC transplantation”

Relevant publications

  • Aljitawi OS, “Ex vivo expansion of umbilical cord blood: where are we?” Int J Hematol. (April 2012).
  • Omar S. Aljitawi et al, “Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34+ cells in a murine model of umbilical cord blood transplantation.” Blood Cells Mol Dis. (Aug 2013).