Effects of Circulating Factors and Progenitors on Wound Healing during Pregnancy

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Abstract: Wound healing is a complex biological process requiring growth factors and progenitor cells that act in concert to restore the integrity of the injured tissue. Fibrosis or scarring of tissue results from nonspecific repair as well as aberrant wound healing in response to tissue injury and not only predisposes tissue to a secondary injury but also contributes to 45–50% of deaths in the Western world. Increased age is a major risk factor for impaired wound healing due to tissue fibrosis. Many studies at the cellular and molecular level have examined age-related differences in wound healing and have identified an age-related decline in progenitor cells. It has been reported that exposure to factors present in the serum of young mice restores the regenerative capacity of aged progenitor cells. Also, fetal dermis has been shown to regenerate after injury without scarring, while adult skin wound healing usually results in scar tissue. Pregnancy represents a unique biological model of a naturally-shared circulatory system between young and old organisms. Our preliminary data have demonstrated improved muscle healing after injury in pregnant mice. More importantly, we have observed an improved myogenic differentiation capacity of aged muscle progenitor cells (MPCs) after stimulation with serum from pregnant mice, suggesting that circulating factors may influence the potency of stem cells in the mother during pregnancy. We hypothesize that circulating factors during pregnancy have beneficial effects on maternal wound healing, such as reduction in fibrosis for optimal tissue regeneration. Therefore, we propose, in Aim1, to determine whether pregnancy accelerates wound healing (skeletal muscle and skin) and which circulating factors in pregnancy are responsible for this beneficial effect. We will utilize previously described skin wound and muscle injury mouse models and adapt them to investigate the healing process, including fibrosis and contributing circulating factors, during pregnancy. In addition, we will obtain skin biopsies from pregnant and non-pregnant women after surgery to analyze tissue healing with respect to scarring at the biopsy site. It has been reported that fetal microchimeric cells (FMCs) can be found in the circulation and organs of mammals during pregnancy as a result of bidirectional passage of maternal and fetal cells. The presence of fetal cells in maternal circulation may play a beneficial role in repairing damaged maternal tissues. Little has been done to determine the exact roles of circulating fetal progenitor cells and how they interact with maternal progenitor cells during pregnancy with respect to wound healing. In Aim 2, we propose to determine which circulating fetal and maternal progenitor cells in pregnant mice are responsible for the beneficial effects on wound healing during pregnancy. Green fluorescent protein (GFP)- expressing male mice will be crossed with female mice without GFP, and GFP will be used to track FMCs. The Y chromosome will be used as an additional method to track the FMCs. Results from this study will identify rejuvenating factors and novel progenitor cells within blood circulation during pregnancy with potential for development of novel and clinically relevant therapies to improve wound healing and reduce fibrosis.