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Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis

Shahram Aarabi^*,1, Kirit A. Bhatt^*,1, Yubin Shi^*, Josemaria Paterno^*, Edward I. Chang^*, Shang A. Loh^*, Jeffrey W. Holmes, Michael T. Longaker^*, Herman Yee and Geoffrey C. Gurtner^*,2

^* Department of Surgery, Stanford University School of Medicine, Stanford, California, USA; and

Department of Biomedical Engineering, Columbia University, and

Department of Pathology, New York University School of Medicine, New York, New York, USA.

²Correspondence: Stanford University, PSRL, GK-210, 257 Campus Dr., Stanford, CA 94305-5148, ggurtner{at}stanford.edu

Hypertrophic scars occur following cutaneous wounding and result in severe functional and esthetic defects. The pathophysiology of this process remains unknown. Here, we demonstrate for the first time that mechanical stress applied to a healing wound is sufficient to produce hypertrophic scars in mice. The resulting scars are histopathologically identical to human hypertrophic scars and persist for more than six months following a brief (one-week) period of augmented mechanical stress during the proliferative phase of wound healing. Resulting scars are structurally identical to human hypertrophic scars and showed dramatic increases in volume (20-fold) and cellular density (20-fold). The increased cellularity is accompanied by a four-fold decrease in cellular apoptosis and increased activation of the prosurvival marker Akt. To clarify the importance of apoptosis in hypertrophic scar formation, we examine the effects of mechanical loading on cutaneous wounds of animals with altered pathways of cellular apoptosis. In p53-null mice, with down-regulated cellular apoptosis, we observe significantly greater scar hypertrophy and cellular density. Conversely, scar hypertrophy and cellular density are significantly reduced in proapoptotic BclII-null mice. We conclude that mechanical loading early in the proliferative phase of wound healing produces hypertrophic scars by inhibiting cellular apoptosis through an Akt-dependent mechanism.—Aarabi, S., Bhatt, K. A., Shi, Y., Paterno, J., Chang, E. I., Loh, S. A., Holmes, J. W., Longaker, M. T., Yee, H., Gurtner, G. C. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis.

Key Words: hypertrophic scar • wound healing • fibrosis • scarring