Red Blood Cell Formation in Humans Differs From Animal Models

Northwestern Medicine scientists have discovered that one of the body’s most fundamental biological processes - how red blood cells are made - works differently in humans than previously thought, according to a new study published in Nature Genetics.

The findings overturn decades of assumptions based largely on animal research, said study senior author Peng Ji, MD, PhD, the Marie A. Fleming Research Professor of Pathology.

In the study, Ji and his collaborators used advanced spatial mapping tools to directly observe microscopic environments, known as erythroblastic islands (EBIs), inside intact tissues. EBIs have long been understood to act as “nurseries” where red blood cells mature. But until now, scientists lacked a clear picture of what these structures look like in humans.

“For decades, our understanding of these structures has come almost entirely from mouse studies,” said Ji, who is also vice chair for research in the Department of Pathology. “Most experiments relied on isolating cells and studying them in flat, two-dimensional systems, which disrupt their native organization.”

To overcome those limitations, the team used spatial transcriptomics, a technology that maps gene activity within whole tissue. This allowed them to preserve the natural structure of EBIs while comparing mouse and human samples directly.  

They found that in mice, the conventional model still applies: EBIs form around a macrophage (a kind of specialized 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.

But in humans, investigators found there was no organizing center. Instead, red blood cells form clusters independently, sticking to each other via a molecule called ICAM4.

“The most surprising finding is that the structure of these niches is species-specific,” Ji said. “In humans, the erythroid cells cluster on their own without needing a central macrophage. That overturns a long-standing assumption that human blood formation mirrors what we see in mice.”

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.”

When the investigators examined bone marrow samples from patients with myelodysplastic syndromes (MDS), a blood disease that often manifests as anemia, they found that these human cell clusters were disrupted but could be partially restored with treatment.  

That suggests the structure of EBIs may influence disease progression and recovery.