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Mechanism for how organs branch found

The lung is as much a natural work of art as a functioning organ with its twisting bronchial branches and delicate curls. Now Princeton researchers observing growth in mouse embryo lungs, arrive at a surprising idea of forces that help shape lungs.

In a series of recent experiments, researchers in the lab of Celeste Nelson PhD, professor of chemical and biological engineering, have found that airway branching in the developing lung is regulated in part by mechanical forces experienced by embryonic tissues. This insight expands the standard theory that airway branching is controlled by a closed genetic program, hardwired in DNA.

"Our work indicates that physical forces can determine the locations where new branches form within the developing lung" says Victor Varner, a post-doctoral scientist in chemical and biological engineering, and lead author on one of two papers recently published on the subject.

The results help us understand developmental disorders in babies and have implications for treating growth disorders found in cancer, and the potential for developing lab-grown replacements for other human organs.

"Our work underlines the fact that tissues and organs are physical objects sculpted in the embryo by mechanical forces."

Celeste Nelson PhD, Professor, Chemical and Biological Engineering, Princeton University, New Jersey, USA

The lung's array of twisting branches may appear to be random, but follow a consistent pattern. Previous work in this field has suggested lung pattern is determined by distribution of biochemical molecules within the embryonic lung tissue — following one particular molecule, FGF 10 (fibroblast growth factor), thought to direct development and branching in airways.

Varner and Nelson wondered if biochemical signals were the only way to control airway branching. In one experiment, they dissected a small piece of lung tissue from an early mouse embryo and separated the developing airways from the adjacent cells expressing FGF10, thereby disrupting the biochemical pre-pattern thought to control the formation of new branches. These fragments of developing airway were then cultured in a three-dimensional gel and, remarkably, continued to grow and branch in the laboratory.

"Once we'd disrupted the pre-pattern growth factors, given my background as a mechanical engineer, I wondered if a physical mechanism might controll the formation of new branches in culture,"added Victor Varner, a post-doctoral student in chemical and biological engineering in Nelson's laboratory.

The article on the study was published on July 28, 2015, in the Proceedings of the National Academy of Sciences or PNAS1.

Varner said the researchers determined that a mechanical instability, similar to the buckling of a beam or column under compressive force, was generated within the growing airway and that this instability dictated where new branches formed along the tissue.

"This work highlights the role of mechanical forces during development. In addition to biochemical signaling, physical cues also control how developing organs self-assemble in an embryo."

Victor Varner, post-doctoral student in chemical and biological engineering

For their next experiment, the researchers want to examine how mechanical stresses affect branching in the intact embryonic lung, a far more complex environment than a simplified 3D culture. Eventually, they hope to find how physical forces contribute to underlying congenital branching defects.

In a related but separate study, Nelson's lab scientists also determined that bifurcations in the developing lung are sculpted by a layer of smooth muscle wrapping around the airways. This work, published Sept. 28, 2015, in Developmental Cell2, used transgenic mice, with smooth muscle cells that glow fluorescently whenever expressed. This enabled them to track the motion of smooth muscle cells dynamically in culture.

Nelson and colleagues found smooth muscle cells accumulate in the cleft at the tip of newly forming bifurcations — pulling the tube into two new daughter branches. Investigating further, researchers found that when smooth muscle growth was disrupted, airways no longer split into two branches.

According to Nelson, these results highlight the role of mechanical forces in lung development while also revealing that smooth muscle "acts like a girdle forcing developing airways into shape."

1 PNAS: Mechanically patterning the embryonic airway epithelium
During branching morphogenesis of the developing lung, it is generally thought that a spatial template of biochemical cues determines the airway branching pattern. Here, however, we demonstrate that physical mechanisms can control the pattern of airway branching. Using a combination of 3D culture experiments and theoretical modeling, we show that a growth-induced physical instability initiates the formation of new epithelial branches. Tuning epithelial growth rate controls the dominant wavelength of the instability, and thereby the branching pattern. These findings emphasize the role of mechanical forces during morphogenesis and indicate that lung development is not a closed genetic system. Physical cues also regulate the spatially patterned cell behaviors that underlie organ assembly in the embryo.

Collections of cells must be patterned spatially during embryonic development to generate the intricate architectures of mature tissues. In several cases, including the formation of the branched airways of the lung, reciprocal signaling between an epithelium and its surrounding mesenchyme helps generate these spatial patterns. Several molecular signals are thought to interact via reaction-diffusion kinetics to create distinct biochemical patterns, which act as molecular precursors to actual, physical patterns of biological structure and function. Here, however, we show that purely physical mechanisms can drive spatial patterning within embryonic epithelia. Specifically, we find that a growth-induced physical instability defines the relative locations of branches within the developing murine airway epithelium in the absence of mesenchyme. The dominant wavelength of this instability determines the branching pattern and is controlled by epithelial growth rates. These data suggest that physical mechanisms can create the biological patterns that underlie tissue morphogenesis in the embryo.

In addition to Nelson and Varner, the authors of the PNAS article included: James Gleghorn, a postdoctoral researcher in chemical and biological engineering at Princeton; Erin Miller and Derek Radisky of the Mayo Clinic Cancer Center. The research was supported in part by the National Institutes of Health, the National Science Foundation, the David and Lucile Packard Foundation, the Alfred P. Sloan Foundation, and the Camille and Henry Dreyfus Foundation.

Besides Nelson and Varner, the authors of the Developmental Cell article included: Hye Young Kim and Mei-Fong Pang, post-doctoral researchers in chemical and biological engineering at Princeton; Lisa Kojima, an undergraduate student in chemical and biological engineering; Erin Miller and Derek Radisky of the Mayo Clinic Cancer Center. The work was supported in part by the National Institutes of Health, the National Science Foundation, the David and Lucile Packard Foundation, the Alfred P. Sloan Foundation, the Camille and Henry Dreyfus Foundation, and Susan G. Komen for the Cure.


2 Developmental Cell: Localized Smooth Muscle Differentiation Is Essential for Epithelial Bifurcation during Branching Morphogenesis of the Mammalian Lung

•Regions of epithelial shape change coincide with differentiating smooth muscle
•Differentiating smooth muscle cells appear at lung bud bifurcation sites
•Blocking differentiation or surgically removing smooth muscle disrupts bifurcation

The airway epithelium develops into a tree-like structure via branching morphogenesis. Here, we show a critical role for localized differentiation of airway smooth muscle during epithelial bifurcation in the embryonic mouse lung. We found that during terminal bifurcation, changes in the geometry of nascent buds coincided with patterned smooth muscle differentiation. Evaluating spatiotemporal dynamics of α-smooth muscle actin (αSMA) in reporter mice revealed that αSMA-expressing cells appear at the basal surface of the future epithelial cleft prior to bifurcation and then increase in density as they wrap around the bifurcating bud. Disrupting this stereotyped pattern of smooth muscle differentiation prevents terminal bifurcation. Our results reveal stereotyped differentiation of airway smooth muscle adjacent to nascent epithelial buds and suggest that localized smooth muscle wrapping at the cleft site is required for terminal bifurcation during airway branching morphogenesis.

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Delicate branching in growing lung tissue is
partly controlled by mechanical forces,
Image Credit: Nelson Lab, Princeton University

How lung tubules biforcate into bronchiol tubes
Image Credit: Nelson Lab, Princeton University




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