Made in Canada solutions for the scarcity of stem cell donors?

Author: Sara M. Nolte, 08/08/16

If you’ve been on social media lately, you’ve probably come across various campaigns looking for stem cell donors. You may even know someone who needs a stem cell transplant. It is increasingly apparent that there is a demand for stem cell donors for those in need.

Who are these people who need stem cell transplants? These are people suffering from blood cancers (leukemia, lymphoma), blood/bone marrow diseases (myelodysplasia, aplastic anemia), or other immune or congenital disorders that prevent their bone marrow from making the blood cells they need to survive (Figure 1). Unfortunately, two out of three people needing a stem cell transplant are unable to have one due to lack of a matching donor.

Figure 1. The hematopoietic hierarchy. Hematopoietic stem cells (HSCs), found in bone marrow, are responsible for producing the various blood cells that are required for life. These include red blood cells (carry oxygen), white blood cells (fight viral and bacterial infections), and platelets (stop bleeding). HSCs possess the property of self-renewal, and initiate the hierarchical cell division process. With subsequent divisions, cells become more specialized in terms of their function, and more limited in their capacity to produce other cell types. Image source: https://commons.wikimedia.org/w/index.php?curid=7351905.

Figure 1. The hematopoietic hierarchy. Hematopoietic stem cells (HSCs), found in bone marrow, are responsible for producing the various blood cells that are required for life. These include red blood cells (carry oxygen), white blood cells (fight viral and bacterial infections), and platelets (stop bleeding). HSCs possess the property of self-renewal, and initiate the hierarchical cell division process. With subsequent divisions, cells become more specialized in terms of their function, and more limited in their capacity to produce other cell types. Image source: https://commons.wikimedia.org/w/index.php?curid=7351905.

 

The “lack of donors” problem isn’t necessarily an indication of a lack of people wanting to be donors. It is more an issue of finding an appropriate ‘match.’ The match for bone marrow transplants is much more complicated than that used for blood donation (i.e. blood types A, B, O, AB). To have a compatible donor, the donor bone marrow must match several of the recipient’s human leukocyte antigens (HLAs). HLAs are inherited genetic markers that help the immune system recognize ‘self’ from ‘not-self.’ These markers become more complex and variable in our population due to the large variety of ethnic backgrounds. This makes it difficult to find appropriate stem cell donors, and family members are often the best option.

One way clinicians have been addressing this issue is to use umbilical cord blood as a source of stem cells. With permission, cord blood (which would otherwise have been discarded, along with the placenta, as waste) is now being collected from umbilical cords after birth and banked for future use. Cord blood is a great source of hematopoietic stem cells (HSCs), is obtained non-invasively, and large banks make it more likely to find compatible donors. Unfortunately, there are limited numbers of HSCs in each cord blood sample, making a single sample insufficient for transplant.

Excitingly, Drs. John Dick (University Health Network, Toronto) and Gerald de Haan (European Institute for the Biology of Ageing, the Netherlands) have published new research in Cell Stem Cell identifying a ‘switch,’ that when turned ‘on,’ can increase the HSC population in cord blood, potentially addressing the current limitations with cord blood (press release with explanatory video featuring Dr. John Dick).

The ‘switch’ of interest is miR-125a: a micro RNA that had previously been implicated in regulating mouse HSC self-renewal (the ability to self-regenerate and produce all blood cell types). As in previous murine studies, they found that miR-125a levels were highest in human cord blood HSCs, and decreased in the progenitor and differentiated cell types. Increasing the amount of miR-125a in HSCs allowed for enhanced self-renewal properties.

The next part of the study involved expressing miR-125a in progenitor cells to see if they could regain the HSC property of self-renewal. Compared to control cells, progenitors forced to express higher levels of miR-125a were successfully transplanted into mice, and produced all blood cell types. Furthermore, they showed that the transplanted miR-125a progenitors could be harvested and transplanted into another set of mice, demonstrating that the regained self-renewal was not transient. The team also took reassuring steps to show that the modified progenitors did not proliferate unchecked (i.e. were not cancerous), and that there were no contaminating HSCs in the transplanted samples that could be giving false-positive results.

To examine how miR-125a could be exerting its self-renewal regulatory effects, protein analyses were performed to determine miR-125a targets. One of which was p38, a negative regulator of self-renewal (i.e. turns self-renewal ‘off’) in HSCs, where inhibition of p38 leads to HSC expansion (i.e. self-renewal is turned ‘on’). This would suggest that one way miR-125a expression induces self-renewal in progenitors is by reducing the amount of p38 in the progenitor cells, thus, limiting its inhibitory signal. Additional miR-125a targets included other proteins that suppress signaling and cell proliferation.

This research is proof-of-concept that inducing self-renewal in progenitors, essentially making them HSC-like, could increase the HSC population in a sample of cord blood. Next steps for this group would involve expanding this concept to clinical-level application.

ExCellThera, a spin-off company from IRICoR and CCRM, led by Drs. Guy Sauvageau (Université de Montreal) and Peter Zandstra (University of Toronto) is using a similar idea of enhancing the HSC population in cord blood. Their model involves using the small molecule UM171 to increase HSC proliferation in combination with an innovative culture system that further enhances growth of the HSC population in cord blood. This technology, currently being tested in a Phase I/II clinical trial, is a promising method of maximizing the effectiveness of using cord blood for stem cell transplants. (Ed: In an earlier blog post, Sara Nolte described the clinical trial and cancer drug approval process in Canada, here.)

While both of these scientific platforms using cord blood samples are certainly exciting and very promising, we have not yet replaced the need for stem cell (bone marrow) donors for patients requiring stem cell transplant. If you are interested in learning more about becoming a stem cell donor, please visit OneMatch (Canadian Blood Services).

 

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Sara M. Nolte

Sara Nolte holds a Bachelor of Health Sciences and Masters of Science in Biochemistry & Biomedical Sciences from McMaster University. Her MSc research focused on developing of cancer stem model to study brain metastases from the lung. She then spent a year working on developing cell-based cancer immunotherapies. Throughout a highly productive graduate career, Sara became interested in scientific communication and education. She is now involved in developing undergraduate programs and courses in the health sciences at McMaster, and is looking for ways to improve scientific communication with the public. Outside of science, Sara enjoys participating in a variety of sports, and is a competitive Olympic weightlifter hoping to compete at the National level soon!

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