In previous posts, I discussed the use of cell therapy, specifically the application of allogenic or autologous hematopoietic stem cells (HSCs), as a way to repopulate blood cell lineages to normal levels post-treatment in patients suffering from certain types of blood-related cancers. These therapies would not be successful if not for the ability of stem cells to home and migrate. All cell therapies rely on the cells to somehow find their way through the body, migrate to the appropriate stem cell niche, and from there, differentiate and repopulate the target system. This process was discussed by Tsvee Lapidot at the recent Annual Meeting for the American Society of Hematology.
During his seminar, Dr. Lapidot discussed the dynamic nature of stem cell niches, the environment in which stem cells are found and regulated. The hematopoietic stem cell niche is found in the bone marrow and formed by a variety of cell types, including stromal cells. Bone marrow stromal cells can maintain HSCs in a quiescent inactive state indefinitely. But sometimes the body needs to replenish its cells, requiring that stem cells be allowed to differentiate and migrate. This suggests that stem cell niches are changeable and one mechanism for this change is through the regulation of a protein called “stromal cell-derived factor-1” (SDF-1).
During a transplant, SDF-1 initially plays a role in the homing process. HSCs in circulation are attracted to the higher concentrations of SDF-1 in the bone marrow and use this concentration gradient to “find their way home”. Once in the bone marrow, stem cell niche interactions take over.
When modeled in mice, human stem cells are found anchored to tissue or unanchored. Here, SDF-1 plays another role: the protein not only attracts HSCs but also mediates their interactions with anchoring molecules. HSCs can become unanchored when the concentration of bone marrow SDF-1 is reduced through the action of a molecule called “granulocyte colony stimulating factor” (GCSF). Without these anchoring interactions, the cells can proliferate, differentiate and migrate into the circulation. And in the clinic, it has been shown that the cells of healthy donors, whether autologous or allogenic, also mobilize when induced in similar conditions. But when do the concentrations of these molecules change?
Bones are dynamic organs, which constantly undergo remodeling and rebuilding through the actions of cells known as osteoclasts. During certain stress-induced situations such as bleeding or infection, these cells are activated. Once activated, osteoclasts induce HSC egress from the bone marrow by secreting HSC attractants into the blood and reducing the bone marrow concentration of SDF-1. And when coupled with GSCF induction, these changes are enough to stimulate HSC mobilization.
Mobilization is the second half of a successful stem cell therapy and is nearly the exact opposite of homing. Instead of finding their way back to the bone marrow, HSCs will begin to leave the bone marrow. Instead of remaining inactive, the HSCs will proliferate and differentiate. Finally, attracted by the higher concentrations of chemical attractants in the bloodstream, they re-enter circulation.
By studying the processes of homing and mobilization, we can attempt to better understand the interactions involved in cell therapy and improve upon it. For example, knowing what stimulates HPC mobilization may allow us to mimic the condition in the clinic and harvest cells more efficiently for transplant. Many more interactions are involved than the ones mentioned here, but further research into this area will have a direct impact on therapies, which rely upon the repopulation of cell lineages via cell therapy.
Image: Cancer Hearts You by Craig Aarts, SCN archives