Frontiers in cell and developmental biology · 2026
Matrix stiffness may drive multi-cellular crosstalk via YAP signaling in biliary atresia liver fibrosis: a mechanistic review.
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Cheng Jiwen
Аннотация
BACKGROUND: Biliary atresia (BA) is a devastating liver disease in infants. It leads to progressive cholangitis and fibrosis. In BA, the liver builds up too much extracellular matrix (ECM) and crosslinks it. That makes the tissue stiffer over time-a physical hallmark of fibrosis.
MECHANISTIC FRAMEWORK: Most of the current evidence comes from non-BA models and lab studies. Those studies hint that higher matrix stiffness might act as a mechanical trigger. It could activate YAP signaling, which then organizes pathological crosstalk among hepatocytes, cholangiocytes, and hepatic stellate cells (HSCs). Direct proof from BA tissue is still missing.
KEY FINDINGS: This review looks at how matrix stiffness-through YAP-driven mechanotransduction-may drive pro-fibrotic changes in hepatocytes, cholangiocytes, and HSCs. We propose a self-reinforcing, multi-cellular pro-fibrotic network: stiff ECM turns on YAP in hepatocytes (which release inflammatory signals) and cholangiocytes (which secrete pro-fibrotic factors). Those activated HSCs then deposit and crosslink even more ECM. That raises stiffness further and locks YAP activation in all 3 cell types. Right now, this model rests mostly on indirect evidence. It needs BA-specific testing.
THERAPEUTIC IMPLICATIONS: We also touch on new strategies that target this mechanobiological circuit-YAP inhibitors and matrix-softening methods.
CONCLUSION: By pulling together what we know about ECM mechanics, YAP mechanotransduction, and cell-cell crosstalk, this review points to the matrix stiffness-YAP axis as a likely key driver of BA fibrosis. It also looks like a promising treatment target.
MECHANISTIC FRAMEWORK: Most of the current evidence comes from non-BA models and lab studies. Those studies hint that higher matrix stiffness might act as a mechanical trigger. It could activate YAP signaling, which then organizes pathological crosstalk among hepatocytes, cholangiocytes, and hepatic stellate cells (HSCs). Direct proof from BA tissue is still missing.
KEY FINDINGS: This review looks at how matrix stiffness-through YAP-driven mechanotransduction-may drive pro-fibrotic changes in hepatocytes, cholangiocytes, and HSCs. We propose a self-reinforcing, multi-cellular pro-fibrotic network: stiff ECM turns on YAP in hepatocytes (which release inflammatory signals) and cholangiocytes (which secrete pro-fibrotic factors). Those activated HSCs then deposit and crosslink even more ECM. That raises stiffness further and locks YAP activation in all 3 cell types. Right now, this model rests mostly on indirect evidence. It needs BA-specific testing.
THERAPEUTIC IMPLICATIONS: We also touch on new strategies that target this mechanobiological circuit-YAP inhibitors and matrix-softening methods.
CONCLUSION: By pulling together what we know about ECM mechanics, YAP mechanotransduction, and cell-cell crosstalk, this review points to the matrix stiffness-YAP axis as a likely key driver of BA fibrosis. It also looks like a promising treatment target.