Impact of intracellular control over macrophage phenotype transitions on angiogenesis and wound healing

• Applicant: Dr. Tina Tylek
• Subject Area: Immunology ; Biomaterials
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 445352816

Impaired wound healing, as in chronic wounds of diabetic conditions, is a major burden of patients and the economic health system. The primary underpinnings of non-healing wounds are a prolonged inflammatory state and defective angiogenesis. Although macrophages, key players of the inflammatory response, are known to regulate angiogenesis, the mechanisms behind how impaired inflammation leads to impaired angiogenesis are not understood. In addition, chronic wounds show a delayed appearance of macrophages of the pro-inflammatory M1 type as well as a diminished recruitment of pro-healing M2 macrophages. However, most studies so far focused only on the importance of M2 type macrophages in wound healing and angiogenesis, and majorly did not consider the importance of the M1 phase for the regulated timeline of their appearance. Thus, it is not known how the delayed M1 presence impacts the subsequent arrival and polarization of M2 macrophages. Therefore, in-depth studies of these processes are needed to enable the design of functional macrophage-based therapies as treatment options for diseases. Recent findings of Dr. Spiller’s group showed that macrophages that undergo a direct transition from M1 macrophages to the M2 type (so-called M1-M2 macrophages) were more angiogenic and less fibrotic than those which differentiated from unactivated M0 macrophages in vitro. In chronic wounds, the deficit of this M1-M2 macrophage type is most likely a major contributor to the observed defective wound healing. Therefore, the overarching goal of this project is to investigate how the transition from M1 to M2 type macrophages affects angiogenic processes in normal and delayed healing. To address this question, a macrophage-based cell therapy strategy will be developed in which engulfed microparticles will be utilized for intracellular control of the transition of pre-polarized M1 macrophages into the M2 type. This strategy may allow for both augmenting the macrophage population and retaining their critical polarization timeline. A 3D tissue-engineered model of vascularization and angiogenesis will determine the effects of the controlled M1-M2 transition on vessel formation and macrophage-endothelial cell interaction in vitro. This translational strategy will be evaluated in vivo in a cutaneous wound model in diabetic and wildtype mice. It is expected that the biomaterial-mediated cell therapy strategy developed in this study will be advantageous for overcoming impaired healing and defective angiogenesis in chronic wounds by augmentation of the pro-healing and pro-angiogenic macrophage phenotype without neglecting the important early inflammatory response. Therefore, the results of this project will be of high clinical relevance.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Kara Spiller, Ph.D.