Manufacturing of red blood cells by the human body works differently than previously thought, scientists have discovered.
The findings overturn decades of assumptions based largely on animal research, according to study leader Dr. Peng Ji of the Feinberg School of Medicine of Northwestern University in Chicago.
Ji’s team used advanced microscopic techniques to directly observe so-called erythroblastic islands, which have long been understood to act as "nurseries" where red blood cells mature.
"For decades, our understanding of these structures has come almost entirely from mouse studies," Ji said in a statement. "Most experiments relied on isolating cells and studying them in flat, two-dimensional systems, which disrupt their native organization."
For this study, the researchers were able to preserve the natural structure of erythroblastic islands while comparing mouse and human samples directly.
The findings in mice were unsurprising: the erythroblastic islands formed around a specialized macrophage, or white blood cell, marked by the protein C1q, which sits at the center of clusters of developing red blood cells and helps clean up cellular debris.
In humans, there was no organizing center.
"In humans, the erythroid cells cluster on their own without needing a central macrophage,” Ji said. "That overturns a long-standing assumption that human blood formation mirrors what we see in mice."
In a report of the findings published in the journal Cell, the researchers say the discovery represents a fundamental shift in understanding how the body produces its most abundant cell type.
"This is essentially a paradigm shift," Ji said. "Much of biomedical research depends on mouse models. If the underlying biology is different, that affects how we interpret disease mechanisms and develop therapies."
The findings also raise new questions about how the human body compensates for the absence of a central macrophage. In mice, macrophages play a critical role in clearing the nuclei expelled during red blood cell maturation.
Future research will focus on that and other questions, Ji said.
