Exosomes from Hypoxia Preconditioned Muscle‐Derived Stem Cells Enhance Cell‐Free Corpus Cavernosa Angiogenesis and Reproductive Function Recovery

Abstract Tissue engineering for penile corpora cavernosa defects requires microvascular system reconstruction.GelMA hydrogels show promise for tissue regeneration. However, using stem cells faces challenges such as immune rejection, limited proliferation and differentiation, and biosafety concerns. Therefore, acellular tissue regeneration may avoid these issues. Exosomes are used from muscle‐derived stem cells (MDSCs) to modify 3D‐printed hydrogel scaffolds for acellular tissue regeneration. Hypoxia‐preconditioned MDSC‐derived exosomes are obtained to enhance the therapeutic effect. In contrast to normoxic exosomes (N‐Exos), hypoxic exosomes (H‐Exos) are found to markedly enhance the proliferation, migration, and capillary‐like tube formation of human umbilical vein endothelial cells (HUVECs). High‐throughput sequencing analysis of miRNAs isolated from both N‐Exos and H‐Exos revealed a significant upregulation of miR‐21‐5p in H‐Exos following hypoxic preconditioning. Further validation demonstrated that the miR‐21‐5p/PDCD4 pathway promoted the proliferation of HUVECs. Epigallocatechin gallate (EGCG) is introduced to improve the mechanical properties and biocompatibility of GelMA hydrogels. EGCG‐GelMA scaffolds loaded with different types of Exos are transplanted to repair rabbit penile corpora cavernosa defects, observed the blood flow and repair status of the defect site through color Doppler ultrasound and magnetic resonance imaging, and ultimately restored the rabbit penile erection function and successfully bred offspring. Thus, acellular hydrogel scaffolds offer an effective treatment for penile corpora cavernosa defects.