Tube-shaped structures are prominent features of many organs and tissues, including the kidneys, pancreas, lungs, most glands, and the circulatory system. Although researchers can successfully steer stem cells in the lab to form many cell and tissue types, generating whole organs has remained a challenge, partly due to a lack of understanding about how tubular parts form, connect, and are maintained.

Solving that mystery could potentially help researchers generate organs for transplant, ending critical shortages of donor organs and potentially saving thousands of lives – 17 people die each day awaiting a transplant in the U.S.

Ondine Cleaver, Ph.D., Professor of Molecular Biology, has focused her career on deciphering this conundrum, with findings over the last two decades showing that the natural processes that create biological tubular structures rely on three key factors: a cell’s cytoskeleton (an internal network of proteins responsible for cell movement and migration), cell shape, and correctly placed adhesions between neighboring cells.

“I’m driven every day by a deep curiosity about the molecules that govern how cells interact with one another within an organ, how they adopt specialized functions, and how they sustain these roles throughout life and into old age,” she said.

Dr. Cleaver will detail her research April 24 as the next speaker in the 2025 President’s Lecture Series. The 4 p.m. lecture, titled “From Tubes to Tissues: The Cellular Choreography of Organ Formation,” will take place in the Tom and Lula Gooch Auditorium.

Dr. Cleaver discovered her love of science as an undergraduate at the University of Texas at Austin, where her father was a faculty member. Originally planning to study history, she became fascinated by molecular biology. An introductory class taught by a developmental biologist, whose research focused on differentiation – the process by which a single fertilized egg divides and gives rise to the many specialized cell types that make up a mature organism – further captured her interest in this field.

For her graduate education, Dr. Cleaver remained at UT Austin working under the mentorship of Paul Krieg, Ph.D., a developmental biologist. Dr. Krieg and his team studied how the heart and vascular system forms, using frogs as a model system. While investigating a gene called Flk-1 that was thought to play a role in the development of the endocardium (the heart’s inner lining), Dr. Cleaver learned this gene is expressed robustly in cells that are precursors to blood vessels and is necessary for their formation.

After six years and 10 published articles, Dr. Cleaver earned her doctoral degree and left Dr. Krieg’s lab for a postdoctoral fellowship at Harvard University. Working with world-renowned stem cell researcher Douglas Melton, Ph.D., Dr. Cleaver and her colleagues discovered the early tissues that act as precursors for the pancreas and molecular cues necessary for the healthy formation of this organ. Integrating her knowledge of the vasculature, she showed that signals from blood vessels are critical for the formation of pancreatic beta cells that produce insulin.

This work led Dr. Cleaver to a faculty position at UT Southwestern in 2004. Since then, she has made numerous discoveries toward understanding how blood vessels and organs made of tubes and tubules form. In 2011, she and her team reported that a small protein called Rasip1 regulates cytoskeleton movement and cell adhesion and is critical for forming the hollow interiors of blood vessels; when the researchers deleted the gene for this protein in mouse embryos, their blood vessels formed as solid linear cords rather than open tubes.

In another study published in 2017, Dr. Cleaver and her team showed that a Rasip1-related protein called Afadin, critical for making connections between cells called junctions, works with a cytoskeleton-related protein called RhoA to form the hollow interior of the pancreatic tubules. Without the coordinated action of these two proteins, her team discovered, the rudimentary organ that develops has severe defects in the cells that produce insulin.

More recently, studies from the Cleaver Lab have shown that blood vessels sense blood flow, which provides an essential stimulus for their maturation during development and for maintaining healthy function in adulthood. Absence of blood flow in engineered tissues leads to rapid regression of vessels and tissue cell death. The findings could eventually help researchers develop new treatments to improve blood flow in the heart muscle after a heart attack and to grow organs in a lab that can readily connect to a patient’s circulatory system.

“Someday we may be able to train stem cells to become tissue that we can implant into a patient, connect with their vasculature, and have it serve a vital function in their body. Our lab is working toward that goal,” Dr. Cleaver said.