Modulating the stiffness of haematopoietic stem cells could help the mobilisation procedures used for stem cell-based transplants, researchers have reported.
Bone marrow transplants, undertaken as part of cancer treatment, do not normally involve physically extracting bone marrow. Instead, G-CSF is used to encourage blood-forming stem cells to leave the bone marrow and enter the blood. However, about one third of patients find that mobilisation is insufficient.
Scientists at Winship Cancer Institute of Emory University, Children's Healthcare of Atlanta and Georgia Tech, USA, say temporarily reshaping a cell could help to drive blood-forming stem cells out of the bone marrow and into the blood. However, the cells need to remain stiff to remain in the bone marrow niche and replenish the blood and immune system.
Publishing the results of their animal study in the journal Cell Stem Cell, lead author Dr Cheng-Kui Qu, professor of paediatrics at Emory University School of Medicine, says the deformability of cells plays an important role in retaining stem cells in their marrow niches. The research demonstrates how alterations in blood stem cell biomechanics can be associated with certain blood disorders, he added.
Qu and colleagues studied the Ptpn21 enzyme, which is highly expressed in blood stem cells and helps reshape parts of a cell's internal skeleton. They generated mice lacking the Ptpn21 gene, and found that the mutant mice were sensitive to chemotherapy drugs. In addition, the use of G‑CSF lead to much higher numbers of stem cells in the peripheral blood in the Ptpn21 knockout mice, compared to normal mice.
The researchers went on to establish how the loss of Ptpn21 affects cell deformability, discovering that they could make cells lacking Ptpn21 stiff again by interfering with the function of another protein, Septin1.
In addition, they showed that treating normal mice with blebbistatin, which interferes with parts of a cell's internal skeleton, also resulted in mobilisation of stem cells into the blood.
“Our findings are that normal blood-forming stem cells are stiffer and less deformable than differentiated blood cells,” Dr Qu says.
“This helps us better understand the pathogenesis of blood disorders associated with loss of stem cell quiescence. In addition, our findings suggest that cell biomechanics can be leveraged to improve current mobilisation regimens for stem cell-based therapy.”
Ni, F., Yu, W.M., Wang, X., Fay, M.E., Young, K.M., Qiu, Y., Lam, W.A., Sulchek, T.A., Cheng, T., Scadden, D.T., Qu, C.K. (2019) “Ptpn21 Controls Hematopoietic Stem Cell Homeostasis and Biomechanics”, Cell Stem Cell, available at doi: 10.1016/j.stem.2019.02.009