Better Defining Blood Stem Cells to Help Refine Treatments
As we develop and age, some of our tissues are replenished and repaired by adult, or tissue-specific, stem cells. These are specialized cells required throughout life that have the potential to give rise to all types of cells in a given tissue.
Distinct tissues have unique types of adult stem cells. For example, hematopoietic stem cells (HSCs), also known as blood stem cells, give rise to all cell types in the blood and immune system. Strikingly, blood stem cells can be transplanted between individuals, and the healthy stem cells of the donor can replace the damaged cells of the recipient, leading to life-long replacement of the entire blood system. This principle underlies bone marrow transplantation, the most established stem cell therapy. Bone marrow transplantation is now routine and profoundly impacts the survival of patients with blood diseases, cancers and immunodeficiencies that were once considered incurable.
Although blood stem cells are arguably the best understood tissue-specific stem cells in our body, there are still gaps in our fundamental knowledge of these cells and their clinical application. For example, most of the cells used for transplantation will not contribute to replacing the host blood cells, impacting the effectiveness of the transplants, and we also don’t know how to maintain blood stem cells in the lab.
A recent study by Stefan Radtke et al in Science Translational Medicine (2017) suggests that there are functionally-unique subsets of HSCs with differences that could impact the clinical use and study of HSCs.
The current concept of blood and immune system replacement through transplantation is thought to rely on two waves of cells, a short-term and long-term wave, which require two different types of cells. Blood progenitor cells, the HSC-derived subset of cells with a limited lifespan that give rise to specific types of mature blood cells, carry out the immediate, short-term recovery, ensuring that the patient will make it through the treatment. HSCs are responsible for the long-term recovery that gives rise to all types of blood cells.
Data from Radtke and colleagues challenge this process by demonstrating that there are specialized populations of stem cells that can directly repopulate the tissue without progenitor cells. The team at the Fred Hutchinson Cancer Center in Seattle identified one subset of HSCs that robustly contributes to both the initial rapid recovery and long-term reconstitution. The impact of this surprising discovery has significant clinical implications.
Radtke and colleagues first used cell surface markers, unique proteins that tag different cell types, to identify and separate different blood cell populations in the bone marrow of nonhuman primates. The isolated cell populations were then genetically ‘marked’ so that each cell had a unique fingerprint. This technique allowed researchers to track the fate of individually transplanted cells over extended periods of time.
The marked cells were then transplanted into recipients, the standard to assess “stemness,” and the ability of the cells to restore the hematopoietic system was analyzed. Remarkably, one of the transplanted populations was particularly robust at engrafting and giving rise to all the different blood cell types. They also found that different mature blood cell types such as B-cells, T-cells, granulocytes and monocytes, carried an identical fingerprint, demonstrating that they all originated from one and the same engrafted stem cell.
The researchers then reanalyzed data from nonhuman primates who had been given a transplant up to 7.5 years prior. Researchers discovered that one particular HSC subset was present in both short and long-term recovery, indicating that, contrary to the two-wave theory of hematopoietic rebuilding, some stem cells support both rapid repair immediately after transplantation, and long-term maintenance over a period of more than seven years. Researchers also demonstrated that a similar subset of HSCs is present in human blood from umbilical cord and adults. These findings may become a useful strategy to efficiently identify and isolate blood stem cells for human patient therapy.
The Radtke et al study provides an opportunity to fine-tune and improve strategies for stem cell-based therapies. By specifically refining the identity of a blood stem cell, scientists may be able to enrich and isolate the stem cells that can more effectively repopulate the blood system of a sick patient. This will help reduce the number of cells needed for transplantation and improve the efficiency of the procedure, and improve the ability to grow HSCs in the lab. The capability to purify functionally transplantable HSCs has many implications for HSC production, gene therapy, gene editing, and ultimately, bone marrow transplantation.