Cells that are the body's first defense against infection may play role in developing embryo
2013 HSCI Internship Program participant Isaura Frost, who worked on this project, with her mentor postdoctoral fellow Virginie Esain, PhD, at the HSCI intern poster session. (Credit: Trista North, PhD)
Harvard Stem Cell Institute (HSCI) scientists at Beth Israel Deaconess Medical Center, in collaboration with researchers at the University of Pennsylvania, have a new theory for why early immune cells hang out in the developing embryo, despite the low odds of infection.
Reporting in the journal Genes & Development, the scientists found that blood stem cells in the embryo, which have the ability to make T and B cells and maintain lifelong production of the blood system, are not produced in the absence of early (primitive) immune cells—mainly phagocytes, which in the neonate and adult are normally recruited by inflammatory molecules to gobble up bacteria and viruses.
“No one had really shown why the embryo would waste cellular building blocks and energy making cells that it's probably not going to use for this purpose so early in development,” said Trista North, PhD, co-senior author of the study and an HSCI principal faculty member at Beth Israel Deaconess Medical Center.
"When we knocked out inflammatory signals that influenced the number of phagocytes floating around, we also noticed a difference in the production of blood stem cells," she said. "That's when we really started to wonder if there was actual crosstalk going on."
Looking across species, the researchers found this observation to be true in zebrafish and mouse embryos, as well as human fetal tissue, hinting that they’ve stumbled upon an evolutionarily conserved step in vertebrate development that could teach us more about the origins of our immune system.
North, who is also a Harvard Medical School Assistant Professor of Pathology, and her postdoctoral fellow Virginie Esain, PhD, led the work in zebrafish, which are useful for developmental biology research because of their external growth, transparency as embryos and fast growth, whereby all organ systems are present and functioning within 48 hours of fertilization.
Fellow co-senior author Nancy Speck, PhD, a Professor of Cell and Developmental Biology at the University of Pennsylvania Perelman School of Medicine, and her postdoctoral fellow Yan Li, PhD, conducted the correlative experiments in mice. And HSCI Principal Faculty member Stuart Orkin, MD, of the Dana-Farber Cancer Institute and Boston Children’s Hospital, examined human tissue.
The Genes & Development paper is also notable because it resulted from direct mentorship between four generations of women in science. During the summer of 2013, HSCI Internship Program participant Isaura Frost, a chemical engineering student at Purdue University, worked with Esain in the North Lab to determine which inflammatory signals influenced blood stem cell populations in zebrafish. Frost helped identify some of the most potent factors, which included interferon γ (gamma).
“I am so grateful and lucky that Trista let me contribute to this project,” said Frost, now a senior a Purdue and planning to attend medical school. “This experience taught me so much about collaborations with other labs, how to plan effective experiments to answer specific questions, and the process of publishing a paper.”
Then, North and Speck, who was North’s graduate school adviser more than 10 years ago, began to collaborate after chatting about their work during a scientific meeting. The two scientists just happened to be studying the role of interferon in blood development, but in different organisms.
“It’s been so much fun, I am incredibly proud of Trista,” said Speck of their first collaboration since North began her own lab. “She had thought so deeply about the signals in the embryo and brought a lot to the intellectual understanding of what’s going on.”
The influence of interferon γ and other factors on blood stem cell development could inspire new strategies for making blood stem cells from embryonic stem cells in the laboratory, a still challenging scientific feat. “Inflammatory signaling could be a missing component,” said Speck.
The researchers next plan to continue studying the biology of this process. “What initiates blood stem cell production is still an open question,” said North. “Interferon γ doesn’t seem to come from the phagocytes and to be fair, we haven’t exactly been able to pin down who starts this ball rolling.”
Cited: Speck, N. A., North, T. E., Li, Y., and Esain, V., et al. Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production. Genes and Development. November 13, 2014. DOI: 10.1101/gad.253302.114