New Stem-Cell Model Reveals How Tissue-Resident Macrophages Develop

Researchers at VIB have built a human stem-cell-based model that recreates an early stage of immune-cell development, revealing how a single progenitor population can generate specialized macrophages throughout the body. The model offers a platform for studying how these processes change in disease and how they might eventually be harnessed for treatment. 

These cells arise very early in development, with some of their earliest precursors forming in the yolk sac, a temporary structure that supports the embryo before organs are fully formed. Tracing their origins in humans has been difficult, since access to embryonic tissue is extremely limited.

In the new study published in Developmental Cell, a team led by Renzo Mancuso and Bart De Strooper worked around this limitation by recreating the early developmental stage in the lab using human pluripotent stem cells. From these cells, they generated a population called inducible yolk sac myeloid progenitors, or iYSMPs, which molecular profiling showed closely resemble progenitors found during early human development.

The team then tested whether these progenitors could reproduce the developmental potential of their embryonic counterparts by transplanting them into mouse models. The human cells colonized several organs and adapted to their local environment, developing into microglia and border-associated macrophages in the brain, and taking on the identity of the macrophages normally found in the liver, heart, and kidney. Single-cell analysis showed that the transplanted cells activated tissue-specific gene programs closely matching those seen in human macrophages from the corresponding organs. The researchers also found that cultures containing more iYSMPs established themselves after transplantation better than cultures containing more mature macrophages, suggesting that keeping the cells in this early progenitor state is important for efficiently generating tissue-resident macrophages.

“What is exciting here is that we can now generate a human progenitor population that not only resembles the cells seen during early development, but also behaves like them,” said Mancuso. “This gives us a way to study, in much greater detail, how these cells develop and how local tissue environments shape their identity.”

Beyond helping researchers understand how human macrophages develop, the work may also have therapeutic implications, potentially providing a starting point for exploring whether damaged or dysfunctional macrophage populations might one day be replaced. “This could be particularly relevant in neurodegenerative diseases such as Alzheimer’s disease or frontotemporal dementia,” added De Strooper. “Microglia and other macrophage populations are increasingly recognized as active contributors to the disease biology of Alzheimer’s. Having a system that lets us study how these cells develop, adapt, and how they potentially are replaced gives us a new way to explore their role in disease.”