PMID- 37331615 OWN - NLM STAT- MEDLINE DCOM- 20230731 LR - 20230807 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 167 DP - 2023 Sep 1 TI - Functionalized human umbilical cord mesenchymal stem cells and injectable HA/Gel hydrogel synergy in endometrial repair and fertility recovery. PG - 205-218 LID - S1742-7061(23)00339-2 [pii] LID - 10.1016/j.actbio.2023.06.013 [doi] AB - Intrauterine adhesions (IUA) caused by endometrial injury are one of the main causes of female infertility. The current treatments for endometrial injury offer limited clinical benefits and cannot improve endometrial receptivity and pregnancy outcomes. Tissue engineering and regenerative medicine are considered potential solutions to address this concern and may offer effective treatment methods for the regeneration of injured human endometrium. Herein, we prepared an injectable hydrogel based on oxidized hyaluronic acid (HA-CHO) and hydrazide-grafted gelatin (Gel-ADH). The injectable hydrogel showed satisfactory biocompatibility when mixed with human umbilical cord mesenchymal stem cells (hUCMSCs). In an endometrial injury rat model, the treatment with hUCMSCs-loaded injectable hydrogel significantly enhanced the thickness of the endometrium and increased the abundance of blood vessels and glands in the injured endometrium compared to the control group. The hUCMSCs-loaded injectable hydrogel treatment significantly reduced endometrial fibrosis, decreased the expression of the pro-inflammatory factors (IL-1beta and IL-6) and increased the expression of the anti-inflammatory factor (IL-10). This treatment induced endometrial VEGF expression by activating the MEK/ERK1/2 signaling pathway. Moreover, this treatment improved endometrial receptivity to the embryo and restored the embryo implantation rate similar to the sham group (48% in the sham group vs 46% in the treatment group), and this treatment achieved pregnancy and live birth in rats with endometrial injury. In addition, we also preliminarily validated the safety of this treatment in the maternal rats and fetuses. Collectively, our study showed that the hUCMSCs-loaded injectable hydrogel hold potential as an effective treatment strategy promoting rapid recovery of endometrial injury, and this hydrogel is a promising biomaterial for regenerative medicine applications. STATEMENT OF SIGNIFICANCE: 1. Oxidized hyaluronic acid (HA-CHO)/hydrazide-grafted gelatin (Gel-ADH) hydrogel combined with human umbilical cord mesenchymal stem cells (hUCMSCs) are effective in improving the regeneration of endometrium in the endometrial injury rat model. 2. The hUCMSCs-loaded hydrogel treatment promotes the expression of endometrial VEGF through MEK/ERK1/2 signaling pathway and regulates the balance of inflammatory factors. 3. The embryo implantation and live birth rates restore to normal level in the endometrial injury rat model, and the hydrogel has no adverse effects on maternal rats, fetuses, and offspring development after the treatments. CI - Copyright (c) 2023 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. FAU - Zhang, Donghai AU - Zhang D AD - Department of Clinical and Translational Research Center, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092 China. FAU - Du, Qianqian AU - Du Q AD - Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China; Chongqing School, University of Chinese Academy of Sciences, Chongqing 400714, China; Department of Biomaterial, College of Life Sciences, Mudanjiang Medical University, Mudanjiang 157011, China. FAU - Li, Cong AU - Li C AD - Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China; Chongqing School, University of Chinese Academy of Sciences, Chongqing 400714, China; Department of Biomaterial, College of Life Sciences, Mudanjiang Medical University, Mudanjiang 157011, China. FAU - Ding, Chuanfeng AU - Ding C AD - Department of Clinical and Translational Research Center, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092 China. FAU - Chen, Junfeng AU - Chen J AD - Department of Clinical and Translational Research Center, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092 China. FAU - He, Yun AU - He Y AD - School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University, Chongqing 400044, China. FAU - Duan, Tao AU - Duan T AD - Department of Obstetrics, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China. FAU - Feng, Qian AU - Feng Q AD - Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China. Electronic address: qianfeng@cqu.edu.cn. FAU - Yu, Yongsheng AU - Yu Y AD - Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Chongqing 400714, China; Chongqing School, University of Chinese Academy of Sciences, Chongqing 400714, China. Electronic address: yuyongsheng@cigit.ac.cn. FAU - Zhou, Qian AU - Zhou Q AD - Department of Clinical and Translational Research Center, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092 China; Department of Reproductive Immunology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China. Electronic address: shzhouqian@tongji.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230617 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Hydrogels) RN - 9000-70-8 (Gelatin) RN - 9004-61-9 (Hyaluronic Acid) RN - 0 (Vascular Endothelial Growth Factor A) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) SB - IM MH - Pregnancy MH - Humans MH - Rats MH - Female MH - Animals MH - *Hydrogels/pharmacology/metabolism MH - Gelatin/pharmacology MH - Hyaluronic Acid/pharmacology/metabolism MH - Vascular Endothelial Growth Factor A/metabolism MH - Endometrium/metabolism MH - *Mesenchymal Stem Cells/metabolism MH - Umbilical Cord MH - Fertility MH - Mitogen-Activated Protein Kinase Kinases/metabolism/pharmacology OTO - NOTNLM OT - Endometrial injury OT - Gelatin OT - Human umbilical cord mesenchymal stem cells OT - Hyaluronic acid OT - Hydrogel COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/06/19 00:42 MHDA- 2023/07/31 06:43 CRDT- 2023/06/18 19:17 PHST- 2023/01/25 00:00 [received] PHST- 2023/05/21 00:00 [revised] PHST- 2023/06/13 00:00 [accepted] PHST- 2023/07/31 06:43 [medline] PHST- 2023/06/19 00:42 [pubmed] PHST- 2023/06/18 19:17 [entrez] AID - S1742-7061(23)00339-2 [pii] AID - 10.1016/j.actbio.2023.06.013 [doi] PST - ppublish SO - Acta Biomater. 2023 Sep 1;167:205-218. doi: 10.1016/j.actbio.2023.06.013. Epub 2023 Jun 17.