If you Google the term “stem cells”, you will be inundated by search results that range from the expected to the truly bizarre. For example, you can find many articles on stem cell research targets such as diabetes, cancer, and heart disease. But you might also read about growing teeth, producing meat strips as a humane method for food production, and, one of my most recent favourites, “Deer antler stem cells” for veterinary applications (we just knew there had to be a reason for such bulky headgear).
It seems as if the whole field has become “pluripotent” in terms of possibilities. And yet, I still find myself frequently writing about one of its oldest members, the haematopoetic stem cell (HSC).
Why do I find HSCs so intriguing? Part of the reason must be that they have been shown to cure a range of cancers (e.g. leukemias) and blood disorders (sickle cell anemia, thalassemia, SCID) in real patients. In fact, they are now even being investigated for treating autoimmune disorders such as systemic lupus erythematosus.
But I think the main reason is that, as with many things in life, we are most intrigued by that which remains elusive. HSCs are great in that when they work, they really work. However, their usage is still frustrated by so many challenges that it is hard not to keep following up on the progress.
To build on a theme that Stacey Johnson began last month, some of the current problems associated with HSCs include:
- Requirement for strict HLA matching (to avoid Graft-vs.-Host-Disease)
- Low HSC numbers recovered from donors
When you consider the fact that many patients require millions of cells for transfusion, often more than the amount that can be collected from a single donor, you can imagine how challenge 3 then exacerbates challenges 1 & 2.
In a recent article published in the journal Blood, researchers from Weill Cornell Medical College describe a potential mechanism to overcome challenge 3.
Their method aims to promote the expansion of HSCs by exposing them to a protein called HOXB4. One of the obstacles with HSC expansion has been that when a cell divides into two new cells, one daughter cell is differentiated while the other is a stem cell (called asymmetric division). This means that with multiple rounds of division, the number of stem cells doesn’t actually increase.
In the past, HSCs genetically engineered to overexpress HOXB4 have shown stem cell proliferation. The novel contribution made by the group at Cornell, however, was that they made a HOXB4 recombinant protein (recombinant meaning created from an altered gene to have a specific function), which was constructed to be extremely stable intracellularly. They found that HSCs treated with their recombinant HOXB4 were able to expand to an even greater extent than those treated with native, unstable HOXB4. This is an important achievement because it obviates the need for genetically altering cells (potentially causing leukemia) as well as repeated administrations of native HOXB4 protein (time and resource consuming).
Ultimately, this study contributes to an enormous effort towards ex vivo expansion of HSCs, including work done by Drs. Guy Sauvageau (UMontreal) and Keith Humphries (UBC). The implications of attaining such a feat will be nothing short of dramatic. Patients won’t have to be matched to multiple donors for their treatment. Rare HLA-type cells could be expanded (this could be useful for HIV treatment), and the cost, safety, and overall feasibility of HSC-based therapies would be improved.
While recombinant HOXB4 isn’t ready for the clinic just yet, stay tuned as I continue to track progress with one of my favourite cell types.
Lee J., Shieh J.H., Zhang J., Liu L., Zhang Y., Eom J.Y., Morrone G., Moore M.A.S. & Zhou P. Improved ex vivo expansion of adult hematopoietic stem cells by overcoming CUL4-mediated degradation of HOXB4, Blood, DOI: 10.1182/blood-2012-09-455204
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