For the last 20 years, researchers have been studying the Hedgehog signaling pathway to understand its role in tissue morphogenesis and cellular proliferation during embryonic development. Hedgehog signaling transmits information to embryonic cells so they can properly differentiate. When this pathway goes awry, however, it can become a cause of developmental abnormalities and cancer.
In his research, Ivan Moskowitz, MD, PhD, at the University of Chicago Medicine Comer Children’s Hospital, has uncovered how defective Hedgehog signaling contributes to congenital heart disease — a discovery that has important ramifications beyond the heart. “The precocious cellular differentiation caused by defective Hedgehog signaling is a novel cellular mechanism that may contribute to birth defects throughout the body,” says Moskowitz. “Developmental abnormalities such as craniofacial anomalies and possibly Down syndrome, linked to deficient Hedgehog signaling, may share this cellular mechanism.”
Moskowitz and his team have shown that Hedgehog signaling normally maintains a pool of cardiac progenitor cells, destined to become part of the heart but retaining immature characteristics such as proliferation and mobility. When the progenitors migrate into the heart, away from the Hedgehog signal, the cardiac progenitor cells differentiate into muscle. But when Hedgehog signaling is inappropriately removed, cardiac progenitor cells differentiate precociously and turn into muscle outside of the heart instead of migrating into the heart to build necessary heart structures. Progenitor cells that do not receive appropriate Hedgehog signals, therefore, never have the opportunity to close holes in the heart because they turn into muscle too early.
By modulating Hedgehog signaling early, we may be able to improve outcomes for children destined to have developmental abnormalities.
Ivan Moskowitz, MD, PhD
The manifestations of Hedgehog signaling in cells have been the source of much disagreement in the field for many years, according to Moskowitz. “Many researchers believe that Hedgehog signaling directly promotes proliferation of progenitor cells. But based on our molecular and genomic studies, we believe that proliferation is a secondary phenomenon to cells being maintained as progenitors.”
In contrast, when Hedgehog signaling is inappropriately maintained, cells remain in a progenitor state. “Activated Hedgehog signaling keeps the differentiation machinery from working,” says Moskowitz. “And progenitors that are inappropriately maintained proliferate.” Thus, cancers affiliated with inappropriately activated Hedgehog signaling, such as basal cell carcinoma and the brain tumor medulloblastoma, may be caused in part by maintaining tissue progenitors that continue to proliferate instead of differentiating.
Understanding when a cell transitions from being a progenitor to a differentiated cell — and the modulation of that process — provides potential avenues for future investigation and interventions. “By modulating Hedgehog signaling early, we may be able to improve outcomes for children destined to have developmental abnormalities. And since progenitor cells in adults are required for cell regeneration, maintenance and tissue homeostasis, we may be able to impact the ability of tissues to regenerate by modulating Hedgehog signaling in the adult,” says Moskowitz. “We still have a tremendous amount of work to do to examine these important possibilities that have potential ramifications for human health.”