HucMSC-Exo Induced N2 Polarization of Neutrophils: Implications for Angiogenesis and Tissue Restoration in Wound Healing

Jiaman Yang,1,2,* Yulin Xie,1,2,* Zhikuan Xia,1,* Shuaifei Ji,3,* Xin Yang,1 Danxia Yue,1 Yuanyuan Liu,1,3 Rongya Yang,1– 3 Yunlong Fan1,3 1Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, Beijing, 100700, People’s Republic of China; 2The Second School of Clinical Medicine, SouThern Medical University, Guangzhou, 510599, People’s Republic of China; 3Chinese PLA Medical School, Beijing, 100853, People’s Republic of China*These authors contributed equally to this workCorrespondence: Rongya Yang, Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, No. 5, Nanmencang Alley, Dongsi Shitiao, Dongcheng District, Beijing, 100700, People’s Republic of China, Email YangRY301hospital@163.com Yunlong Fan, Department of Dermatology, the Seventh Medical Center of Chinese PLA General Hospital, No. 5, Nanmencang alley, Dongsi Shitiao, Dongcheng District, Beijing, 100700, People’s Republic of China, Email FanYL301hospital@163.comBackground: Neutrophils rapidly accumulate in large numbers at sites of tissue damage, exhibiting not only their well-known bactericidal capabilities but also playing crucial roles in angiogenesis and tissue repair. While exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have emerged as a promising therapeutic tool, their exact mechanisms of action remain partly elusive. We hypothesize that HucMSC-Exo treatment may modulate neutrophil phenotypes, thereby significantly influencing wound healing outcomes.Methods: HucMSC-Exo were isolated via ultracentrifugation and subsequently administered through subcutaneous injection into full-thickness cutaneous wounds in mice. To determine the impact of host neutrophils on the healing effects of HucMSC-Exo in skin injuries, strategies including neutrophil depletion and adoptive transfer were employed. Flow cytometry was used to evaluate the proportion of N2 subtype neutr