Jun Shao,Pan Nie,Wende Yang,Rui Guo,Dongbing Ding,Rongpu Liang,Bo Wei,Hongbo Wei
Neurogenic erectile dysfunction (nED) is one of the most common and intractable postoperative complications of rectal and prostate cancer surgery and sometimes accompanies patients lifelong. The transplantation of stem cells has been proved a promising way for treatment. However, the therapeutic efficacy is severely impaired by excessive cell loss and death and poor accumulation in the injury site along with the traditional implantation strategy. Herein, an EPO-loaded multifunctional hydrogel was designed. The hydrogels' adhesive property and mechanical strength were enhanced by adding catechol-catechol adducts, thus significantly improving adipose-derived stem cells (ADSC) retention and rescuing cell loss in the injury site. Meanwhile, the sustained release of EPO effectively ameliorated the viability and paracrine activity of ADSC, leading to enhanced migration of Schwann cells and differentiation of PC12 cells in vivo. On a bilateral cavernous nerve injury rat model, the present stem cell-EPO-hydrogel implanted strategy could significantly alleviate erectile dysfunction. The higher expression of Tuj1 and lower expression of GFAP in the major pelvic ganglia (MPG) indicated the acceleration of neural differentiation while the suppressing development of astrocytes. Also, the combined therapy restored the expression levels of eNOs, nNOs, and α-SMA in penile tissues, suggesting the rehabilitation of the penis. Further analysis of Masson trichrome staining and apoptosis evaluation of the corpus cavernosum showed the preservation of vascular endothelium content and the prevention of penile fibrosis after denervation. Overall, we believe that this combined strategy presents a promising way not only for restoring neurogenic erectile function but also for the clinical translation of stem cell therapy.
Xuefei Xiang,Yufang Yang,Heyou Gao,ZhiYun Chen,JingYi Xie,QingChuan Hu,Yu Wang
Composite scaffolds composed of porous polyurethane (PU) block copolymer and nano-hydroxyapatite (n-HA) have demonstrated significant potential in bone defect repair. However, the co-effect of osteogenesis and angiogenesis during the process of large bone defect repair is still not yet fully understood. Recent research has found that erythropoietin (EPO) is essential for both osteogenesis and angiogenesis, offering a new research direction for bone regeneration strategies. In this study, a polydopamine (pDA)-modified, EPO-functionalized HA/PU scaffold was fabricated, and its physicochemical properties, release kinetics, and effects on bone repair were systematically investigated. In vitro, a co-culture system of human umbilical vein endothelial cells and rat bone marrow mesenchymal stem cells was used to evaluate the scaffold’s effects on cell proliferation, osteogenic, angiogenic, and HIF-1α/ vascular endothelial growth factor (VEGF) pathway. In vivo, the modified composite scaffold was implanted onto the cranial bone defects of Sprague-Dawley rats to assess its efficacy in promoting bone repair and HIF-1α/VEGF pathway. In vitro, the EPO/pDA/HA/PU group showed more three-dimensional cell morphology with prominent pseudopodia, facilitating cell adhesion, and significantly increased mRNA expression of ALP, Runx2, CD31, CD34, HIF-1α and VEGF. In vivo, the EPO/pDA/HA/PU group exhibited the most significant bone regeneration, with micro- computed tomography analysis confirming a significantly higher the ratio of bone tissue volume to total tissue volume (BV/TV) compared to the blank and HA/PU control groups. These results indicated that the modified composite scaffold enabled sustained release of EPO, which upregulated the expression of HIF-1α and VEGF, thereby enhancing osteogenic and angiogenic capabilities both in vitro and in vivo. Our research demonstrated that loading of EPO onto the HA/PU composite scaffold could effectively promote osteogenesis and angiogenesis. HIF-1α/VEGF signaling plays a crucial role in this process. This discovery provides novel insights and methods for using HIF-1α/VEGF as a regulatory target to advance the clinical translation of large bone defects repair.
Summary Red blood cells supply the oxygen required for all human cells and are in demand for emerging blood-loss therapy. Here we identified N6-methyl-2′-deoxyadenosine (6mdA) as an agonist that promotes the hyperproliferation of burst-forming unit erythroid (BFU-E) progenitor cells. In addition, 6mdA represses the apoptosis of erythroid progenitor cells (EPCs). Combined use of with SCF and EPO enabled cultures of isolated BFU-E to be expanded up to 5,000-fold. Transcriptome analysis showed that 6mdA upregulates the expression of the EPC-associated factors c-Kit, Myb, and Gata2 and downregulates that of the erythroid maturation-related transcription factors Gata1, Spi1, and Klf1. Mechanistic studies suggested that 6mdA enhances and prolongs the activation of erythropoiesis-associated master gene c-Kit and its downstream signaling, leading to expansion and accumulation of EPCs. Collectively, we demonstrate that 6mdA can efficiently stimulate the EPC hyperproliferation and provide a new regenerative medicine recipe to improve ex vivo generation of red blood cells.
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