PMID- 36157523 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20220928 IS - 1948-0210 (Print) IS - 1948-0210 (Electronic) IS - 1948-0210 (Linking) VI - 14 IP - 7 DP - 2022 Jul 26 TI - Intratracheal administration of umbilical cord-derived mesenchymal stem cells attenuates hyperoxia-induced multi-organ injury via heme oxygenase-1 and JAK/STAT pathways. PG - 556-576 LID - 10.4252/wjsc.v14.i7.556 [doi] AB - BACKGROUND: Bronchopulmonary dysplasia (BPD) is not merely a chronic lung disease, but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure. Despite advances in current management strategies, limited progress has been made in reducing the BPD-related systemic damage. Meanwhile, although the protective effects of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) or their exosomes on hyperoxia-induced lung injury have been explored by many researchers, the underlying mechanism has not been addressed in detail, and few studies have focused on the therapeutic effect on systemic multiple organ injury. AIM: To investigate whether hUC-MSC intratracheal administration could attenuate hyperoxia-induced lung, heart, and kidney injuries and the underlying regulatory mechanisms. METHODS: Neonatal rats were exposed to hyperoxia (80% O(2)), treated with hUC-MSCs intratracheal (iT) or intraperitoneal (iP) on postnatal day 7, and harvested on postnatal day 21. The tissue sections of the lung, heart, and kidney were analyzed morphometrically. Protein contents of the bronchoalveolar lavage fluid (BALF), myeloperoxidase (MPO) expression, and malondialdehyde (MDA) levels were examined. Pulmonary inflammatory cytokines were measured via enzyme-linked immunosorbent assay. A comparative transcriptomic analysis of differentially expressed genes (DEGs) in lung tissue was conducted via RNA-sequencing. Subsequently, we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target mRNA and proteins related to inflammatory and oxidative responses. RESULTS: iT hUC-MSCs administration improved pulmonary alveolarization and angiogenesis (P < 0.01, P < 0.01, P < 0.001, and P < 0.05 for mean linear intercept, septal counts, vascular medial thickness index, and microvessel density respectively). Meanwhile, treatment with hUC-MSCs iT ame liorated right ventricular hypertrophy (for Fulton's index, P < 0.01), and relieved reduced nephrogenic zone width (P < 0.01) and glomerular diameter (P < 0.001) in kidneys. Among the beneficial effects, a reduction of BALF protein, MPO, and MDA was observed in hUC-MSCs groups (P < 0.01, P < 0.001, and P < 0.05 respectively). Increased pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 expression observed in the hyperoxia group were significantly attenuated by hUC-MSCs administration (P < 0.01, P < 0.001, and P < 0.05 respectively). In addition, we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs iT compared with rats reared in hyperoxia (P < 0.05). Tran scriptomic analysis showed that the DEGs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses, epithelial cell proliferation, and vasculature development. hUC-MSCs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group. hUC-MSCs increased heme oxygenase-1 (HO-1), JAK2, and STAT3 expression, and their phosphorylation in the lung, heart, and kidney (P < 0.05). Remarkably, no significant difference was observed between the iT and iP administration. CONCLUSION: iT hUC-MSCs administration ameliorates hyperoxia-induced lung, heart, and kidney injuries by activating HO-1 expression and JAK/STAT signaling. The therapeutic benefits of local iT and iP administration are equivalent. CI - (c)The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved. FAU - Dong, Na AU - Dong N AD - Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China. FAU - Zhou, Pan-Pan AU - Zhou PP AD - Department of Pediatrics, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China. FAU - Li, Dong AU - Li D AD - Stem Cell and Regenerative Medicine Research Center, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China. FAU - Zhu, Hua-Su AU - Zhu HS AD - Department of Pediatrics, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China. FAU - Liu, Ling-Hong AU - Liu LH AD - Stem Cell and Regenerative Medicine Research Center, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China. FAU - Ma, Hui-Xian AU - Ma HX AD - Stem Cell and Regenerative Medicine Research Center, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China. FAU - Shi, Qing AU - Shi Q AD - Stem Cell and Regenerative Medicine Research Center, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China. FAU - Ju, Xiu-Li AU - Ju XL AD - Department of Pediatrics, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China. AD - Stem Cell and Regenerative Medicine Research Center, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China. jxlqlyy@163.com. LA - eng PT - Journal Article PL - United States TA - World J Stem Cells JT - World journal of stem cells JID - 101535826 PMC - PMC9350625 OTO - NOTNLM OT - Bronchopulmonary dysplasia OT - Heme oxygenase-1 OT - Hyperoxia OT - JAK/STAT pathway OT - Mesenchymal stem cell OT - Multiple organ injury COIS- Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article. EDAT- 2022/09/27 06:00 MHDA- 2022/09/27 06:01 PMCR- 2022/07/26 CRDT- 2022/09/26 17:09 PHST- 2022/03/30 00:00 [received] PHST- 2022/05/04 00:00 [revised] PHST- 2022/06/20 00:00 [accepted] PHST- 2022/09/26 17:09 [entrez] PHST- 2022/09/27 06:00 [pubmed] PHST- 2022/09/27 06:01 [medline] PHST- 2022/07/26 00:00 [pmc-release] AID - 10.4252/wjsc.v14.i7.556 [doi] PST - ppublish SO - World J Stem Cells. 2022 Jul 26;14(7):556-576. doi: 10.4252/wjsc.v14.i7.556.