PHYSICIANS - Center of Biomedical Research Excellence (COBRE)

Projects (ongoing)

Satori Iwamoto, MD, PhD
Use of stem cells in human chronic wounds

In recent years, considerable success in the treatment of non-healing chronic wounds has been achieved with some advanced therapies, including growth factors and tissue engineering products. However, up to 50% of difficult to heal wounds, including venous ulcers of long duration, are unresponsive to treatment. In a pilot study, we have recently shown that topically applied cultured autologous mesenchymal stem cells (MSC) may accelerate healing in difficult to heal human wounds. We obtained a single bone marrow aspirate of 35-50 ml from patients with acute and chronic, long-standing, venous ulcers. Marrow cells were grown in vitro under conditions favoring the propagation of MSC. Flow cytometry, immunostaining, and functional inductive studies showed findings highly consistent with published reports of human MSC. We developed a novel modified fibrin spray system to deliver the cells to the wound. We found a significant direct correlation between the application of MSC and healing. These studies are on-going. However, we are also developing ways to use mobilization of bone marrow stem cells to achieve targeting of stem cells to sites of injury. This will first be done in murine studies, optimizing the reagents and the conditions, with the ultimate goal of achieving proper mobilization and targeting in human chronic wounds. The goal of this proposal is to determine the true potential of stem cells in wound healing. To test the overall hypothesis that stem cells can be safely used for tissue repair, we will perform a clinical randomized controlled trial. This trail will be backed by methods and results using murine studies. Within the context of this clinical trial, we propose the following two specific aims:

1. Determine the effect of stem cells on the healing of human chronic wounds. A clinical trial in patients with venous ulcers will determine the effectiveness of stem cells mobilized from the bone marrow and using G-CSF, compared to control compression treatment alone. A fibrin spray system will be used as additional control to determine the targeting capabilities of fibrin in the context of stem cell therapy. Healing will be assessed by computerized planimetry for wound edge migration and healing rate, wound size reduction, and complete closure.
   
2. Characterize and closely correlate the expression of wound edge molecular markers of impaired healing and epithelial migration in response to treatment. Baseline and sequential biopsies from the edges of venous ulcers treated in specific aim 1 will be used to determine the epidermal expression of c-myc, β-catenin, and keratins 6/16 and 17 at the wounds' edges. These measurements, closely correlated with wound size and edge migration, will help us establish molecular markers involved in impaired healing and whether the MSC may work by affecting the expression and localization of these specific molecular markers.

These studies will determine whether bone marrow-derived stem cells can accelerate closure of difficult to heal wounds, and will prospectively establish the role of promising molecular markers in epidermal migration and healing.