The cells within human organisms are influenced by both chemical and mechanical forces. However, until recently, researchers have had limited understanding of how to manipulate the mechanical aspects of this dynamic. That is about to change.
“This is a significant advancement in our capability to control the cells that contribute to fibrosis,” stated Guy Genin, the Harold and Kathleen Faught Professor of Mechanical Engineering at the McKelvey School of Engineering at Washington University in St. Louis, whose findings were recently published in Nature Materials.
Fibrosis is a condition where cells generate an excess of fibrous tissue. Fibroblast cells perform this function to close wounds, but the process can spread to undesired locations. Notable examples include cardiac fibrosis; fibrosis in the kidneys or liver, which can precede cancer; and pulmonary fibrosis, which may lead to significant scarring and respiratory issues. According to Genin, all soft tissues in the human body, including the brain, have the potential for cells to initiate an unwarranted wound-healing cascade.
The challenge has both chemical and mechanical origins, but mechanical forces appear to have a disproportionately large impact. Researchers at WashU aimed to leverage these mechanical forces, employing a strategic pull and tug in the correct combination of directions to instruct the cell to halt its excessive fiber production.
In their newly released research, Genin and colleagues provide insights into details such as intervention in tension fields at optimal moments to regulate cellular behavior.
“The direction of the tension applied by these cells is crucial in determining their activation state,” stated Nathaniel Huebsch, an associate professor of biomedical engineering at McKelvey Engineering and co-senior author of the study, alongside Genin and Vivek Shenoy at the University of Pennsylvania.
The forces
The human body is perpetually in motion, so it is not surprising that force can encode functions within cells. However, the specific forces, their magnitudes, and their directions are key questions that the Center for Engineering MechanoBiology investigates.
“The intensity of tension influences cellular actions,” Huebsch remarked. However, tension can manifest in various directions. “Our discovery illustrates that the directional nature of stress influences how cells respond,” he added.
Pulling in multiple, nonuniform directions, known as tension anisotropy (think of a taffy pull), is a critical force in initiating fibrosis, as found by the researchers.
“For the first time, we’re demonstrating that by utilizing a tissue structure, we can prevent cell cytoskeletons from taking a route that could result in contraction and subsequent fibrosis,” said Genin.
Huebsch, who developed microscopic models and scaffolds for studying these tension fields affecting cells, clarified that tentacle-like microtubules create tension by extending and projecting in specific directions. The collagen surrounding the cell draws back on these tubules and aligns with them.
“We found that if you disrupt the microtubules, you disrupt the entire organization which could consequently inhibit fibrosis,” remarked Huebsch.
Even though this study focused on understanding the mechanisms that lead to fibrosis, there’s still a lot to uncover about the proper functioning of fibroblasts, especially in the heart, he noted.
“In tissues where fibroblasts are usually well-aligned, what prevents them from entering that wound-healing state?” Huebsch questioned.
Personalized treatment plans
In addition to exploring methods to prevent or treat fibrosis, Genin and Huebsch suggested that physicians could leverage this new understanding of mechanical stress to enhance treatment for injuries or burns. The insights might help mitigate the high failure rate of treatments among elderly patients that require tendon-to-bone or skin-to-skin reattachment.
For example, in cases of rotator cuff injuries, there is strong evidence that patients need to begin moving their arms to regain function, but equally strong evidence that immobilization might be essential for proper recovery. The solution may hinge on the amount of collagen a patient generates and the stress fields affecting the recovery area.
By comprehending the effects of multidirectional stress fields on cellular structures, doctors may be able to tailor individualized treatment plans based on specific patient repairs.
For instance, a patient experiencing biaxial stress from two directions at the injury site might require more exercise to activate cellular repair, said Genin. Conversely, a patient exhibiting uniaxial stress, where the force is applied in only one direction, may risk over-activating cells with any movement, necessitating the immobilization of the injury. All of this and more still needs to be refined and validated, but Genin is eager to begin the journey.
“The next wave of illnesses we aim to tackle are those related to mechanical factors,” Genin asserted.
Alisafaei F, Shakiba D, Hong Y, Ramahdita G, Huang Y, Iannucci LE, Davidson MD, Jafari M, Qian J, Qu C, Ju D, Flory DR, Huang Y-Y, Gupta P, Singamaneni S, Pryse KM, Chao PG, Burdick JA, Lake SP, Elson EL, Huebsch N, Shenoy VB, Genin GM. Tension anisotropy drives fibroblast phenotypic transition by self-reinforcing cell–extracellular matrix mechanical feedback. Nature Materials, online March 25, 2024.
DOI: https:// https://doi.org/10.1038/s41563-025-02162-5
This study was supported by National Science Foundation Center for Engineering Mechanobiology grant CMMI-154857 (G.M.G, V.B.S., and J.A.B.), National Cancer Institute awards R01CA232256 (V.B.S.) and U54CA261694 (V.B.S.), National Institute of Biomedical Imaging and Bioengineering awards R01EB017753 (V.B.S.) and R01EB030876 (V.B.S.), National Institute of Arthritis and Musculoskeletal and Skin Diseases award R01AR077793 (G.M.G.), National Heart, Lung, and Blood Institute award R01HL159094 (N.H), and National Science Foundation grants MRSEC/DMR-1720530 (V.B.S. and J.A.B.) and DMS-1953572 (V.B.S.).
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