Blood Stem Cells Use Mitochondria to Limit Self-Renewal Activity
Published March 2020 | Cell Stem Cell
Hematopoietic stem cells (HSCs) are programmed to renew themselves to sustain life-long production of blood and immune cells. However, HSCs can divide only a limited number of times.
Understanding how HSCs control the pace of their activity could help scientists better manage blood diseases and improve hematopoietic stem cell transplant outcomes.
Now a team of experts at Cincinnati Children’s has uncovered an important clue about how HSC cellular memory works. “We propose that HSCs use mitochondria as a natural checkpoint to remember their divisional history and limit their self-renewal ability,” the co-authors state.
The study was led by co-first authors Ashwini Hinge, PhD, Jingyi He, MD, James Bartram, PhD candidate, and senior author Marie-Dominique Filippi, PhD.
The team found that each time HSCs divide, their energy-producing mitochondria become increasingly dysfunctional. This in turn serves as a form of cellular memory that helps prevent HSCs from excessive replication. Mechanistically, the team reports that this process is controlled by the loss of activity of the mitochondrial fission regulator protein Drp1.
“There are multiple clinical implications from this finding. On the one hand, since overcoming this ‘block’ could lead to cancer, restoring this memory could be a way to reduce outgrowth,” Filippi says. “On the other hand, if we can pharmacologically manipulate this ‘memory’, we could help keep ‘young’ HSCs even after division and thus improve the outcome of transplantation.”
The high-resolution microscopy work involved in this study was difficult, Filippi says, and was made possible by “tremendous” help from Matt Kofron, PhD, director, Confocal Imaging Core. Co-authors Lee Grimes, PhD, and Nathan Salomonis, PhD, were instrumental in the molecular analysis of single cells.
Among several next steps, the team is exploring several pharmacological avenues to help maintain Drp1 functions.
