Investigating Early Blood System Impact on Lifelong Response to Inflammation and Infection
The Collins Laboratory investigates the mechanisms regulating the function and maturation of the blood system in early life in order to determine how those mechanisms shape the ability of neonates to respond to inflammation and infection, a time of particular susceptibility, both during the immediate perinatal period and throughout the lifespan.
We are guided by the hypothesis that rather than simply being “immature,” the hematopoietic stem and progenitor cells (HSPC) responsible for generating and sustaining all immune cells are constrained by unique features of perinatal life, including the immunoregulatory mechanisms that contribute to maternal-fetal tolerance, and the immunological challenge of postnatal exposures such as commensal microbes.
Previously, we established that despite intact myelopoietic potential, fetal HSPCs have reduced myeloid cell production at steady state. In adults, inflammatory signals activate hematopoietic stem cells to overproduce myeloid-biased downstream progenitors, resulting in the large-scale production of mature myeloid cells, in a process known as emergency myelopoiesis. However, in response to inflammation in vivo, fetal HSPCs fail to activate these emergency myelopoiesis pathways, resulting in neutropenia, a hallmark of neonatal sepsis.
We found that the restriction of fetal HSPCs is cell-extrinsic, and identified maternal IL-10 as a key factor limiting fetal emergency myelopoiesis. In its absence, both functional and transcriptional hallmarks of emergency myelopoiesis activation are restored in fetal HSPCs, but this comes at the cost of fetal demise.
The overarching goal of the Collins laboratory will be to follow up on these observations to investigate how early life exposures (including inflammation, infection, microbial colonization, and metabolism) regulate regenerative responses in fetal and neonatal HSPCs, both during the perinatal period and throughout the lifespan.
Join Our Lab
If you are interested in a training position with our lab (clinical trainees, graduate students, post-docs), please contact us!
