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 develop new ways to manage blood diseases and improve the outcomes of stem cell transplants.

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 senior author Marie-Dominique Filippi, PhD, and co-first authors James Bartram, PhD candidate, Jingyi He, MD, and Ashwini Hinge, PhD, and supported by another 10 Cincinnati Children’s co-authors.

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. The team reports that, mechanistically, 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 cancer cells may have overcome this ‘block,’ restoring this memory could be a way to hinder cellular outgrowth,” Filippi says. “On the other hand, having ‘young’ HSCs would be a plus for transplantation. 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 challenging, Filippi says, and was made possible by “tremendous” help from Matt Kofron, PhD, director of the Confocal Imaging Core at Cincinnati Children’s. The single cell RNA-sequencing analyses were made possible by outstanding collaboration with Nathan Salomonis, PhD and Lee Grimes, PhD.

Among several next steps, the team is exploring pharmacological avenues to help maintain Drp1 functions.

“Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition” was published in the March 5, 2020 issue of Cell Stem Cell.

Download printable version