Role of TGF-β1 signaling in spinal cord injury recovery

Spinal cord injury (SCI) often leads to long-term loss of motor and sensory function, with limited available treatment options to restore the lost function. A major challenge in recovery is the formation of scar tissue at the injury site that prevents damaged nerve fibers from regenerating. Glial scarring has been thoroughly investigated, while fibrotic scar formation has been less studied. Transforming growth factor -β1 (TGF-β1), a signaling molecule that regulates inflammation and tissue repair, has been known to play a critical role in fibrosis in many tissues. Understanding how fibrotic scars form could aid in the development of strategies for recovery improvement after SCI.

To better understand the mechanisms underlying fibrotic scar formation after SCI, a research team led by Prof. Xu Cao from the Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA, conducted this comprehensive study. This study, published in Bone Research, Volume 14, Article number 27, on February 25, 2026, reveals that TGF- β1 plays an important role in fibrotic scar tissue formation and limits neural regeneration following SCI. Prof. Cao says, “In adult mice, fibrotic scar formation at injury sites prevents recovery after SCI, and the inhibition of fibrotic scar formation significantly improved SCI recovery.”

The team investigated the cellular changes that take place at the injury site using an SCI mouse model. They observed that macrophages accumulate at the injury site and become a primary source of activated TGF- β1. This activation of TGF- β1 signaling then triggers downstream recruitment of mesenchymal stromal stem cells (MSCs), promoting their differentiation into fibroblasts and subsequently the development of fibrotic scar tissue. The first author, Dr. Dayu Pan mentions, “Overactive TGF-β1 at SCI sites were found to recruit and induce fibroblast differentiation of MSCs, as well as resident pericytes and thus promoting the formation of fibrotic scar.”

Further research revealed that TGF- β1 also regulates the surrounding blood vessels in the injured spinal cord. Prof. Cao explains, “In the blood-spinal cord barrier, activated TGF- β1 acts on resident pericytes in the endothelial niche to promote their differentiation into fibroblasts”. The fibroblasts then produce extracellular matrix components such as collagen and fibronectin, which accumulate at the injury site and lead to the formation of dense fibrotic scar tissue that prevents neural recovery.

Following this, the researchers next examined whether blocking TGF-β1 signaling could reduce fibrotic scar tissue formation. When TGF- β1 was selectively inhibited in the macrophage lineage cells, the injured mice showed significantly reduced fibrotic scar tissue formation and a greater density of nerve fibers in the lesion area. Behavioral tests further revealed improved sensory and motor responses in mice. These findings indicate that restricting macrophage-derived TGF- β1 activity reduces fibrotic scarring and improves functional recovery after SCI. Dr. Pan further explains, “The inhibition of TGF-β1 activity reduced fibrotic scar formation and improved recovery from SCI in mice. Strikingly, neonatal mice did not show TGF-β activity at the SCI site and showed full recovery after injury. Collectively, our findings show that fibrotic scarring results from abnormal TGF-β activity, and that such scarring is the primary obstacle to functional recovery after SCI.”

Interestingly, neonatal mice recovered from SCI without developing fibrotic scarring and showed no active TGF-β1 signaling at the injury site. In contrast, adult mice showed elevated TGF- β1 activation and pronounced fibrotic scarring that limited recovery. The authors suggest that preventing abnormal activation of TGF- β1 or even neutralizing active TGF- β1 may help improve recovery outcomes after SCI.

Lastly, the study highlights the central role of TGF-β1 signaling in fibrotic scar formation and offers new insights into the mechanisms that limit recovery after SCI.

***

 

Reference
DOI: 10.1038/s41413-026-00507-7  

 

About Johns Hopkins University School of Medicine
Website: https://www.jhu.edu/

About Prof. Xu Cao at Johns Hopkins University School of Medicine
Prof. Xu Cao is the Director and the Lee Riley Professor at the Center for Musculoskeletal Research at Johns Hopkins University.

About Dr. Dayu Pan at Johns Hopkins University School of Medicine
Dr. Dayu Pan is a postdoctoral fellow in the Department of Orthopedic Surgery at Johns Hopkins University School of Medicine.

Funding information
This study was conducted at the Johns Hopkins University. This research was supported by the following fundings: NIH National Institute on Aging under Award Number P01AG066603, R01AG076783, and R01AG068997 (to X.C.). Animal behaviour test was facilitated by the Pain Research Core funded by the Blaustein Fund and the Neurosurgery Pain Research Institute at the Johns Hopkins University.

END