Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels
Abstract Background Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs)...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2022-02-01
|
| Series: | Stem Cell Research & Therapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13287-022-02717-2 |
| _version_ | 1818973747373146112 |
|---|---|
| author | Yifeng Lin Shunni Dong Xiaohang Ye Juan Liu Jiaqun Li Yanye Zhang Mixue Tu Siwen Wang Yanyun Ying Ruixue Chen Feixia Wang Feida Ni Jianpeng Chen Binyang Du Dan Zhang |
| author_facet | Yifeng Lin Shunni Dong Xiaohang Ye Juan Liu Jiaqun Li Yanye Zhang Mixue Tu Siwen Wang Yanyun Ying Ruixue Chen Feixia Wang Feida Ni Jianpeng Chen Binyang Du Dan Zhang |
| author_sort | Yifeng Lin |
| collection | DOAJ |
| description | Abstract Background Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms. Methods Ethanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays. Results Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness (P < 0.001, P < 0.05), decrease fibrous area (P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate (P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells. Conclusion Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings. Graphical abstract |
| first_indexed | 2024-12-20T15:29:05Z |
| format | Article |
| id | doaj.art-9eb2edc1c01441bdaaa74887b1c317b9 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-20T15:29:05Z |
| publishDate | 2022-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-9eb2edc1c01441bdaaa74887b1c317b92022-12-21T19:35:40ZengBMCStem Cell Research & Therapy1757-65122022-02-0113111910.1186/s13287-022-02717-2Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogelsYifeng Lin0Shunni Dong1Xiaohang Ye2Juan Liu3Jiaqun Li4Yanye Zhang5Mixue Tu6Siwen Wang7Yanyun Ying8Ruixue Chen9Feixia Wang10Feida Ni11Jianpeng Chen12Binyang Du13Dan Zhang14Key Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineMOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang UniversityKey Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineKey Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineMOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang UniversityKey Laboratory of Women’s Reproductive Health of Zhejiang Province and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of MedicineAbstract Background Thin endometrium is a primary cause of defective endometrial receptivity, resulting in infertility or recurrent miscarriage. Much effort has been devoted toward regenerating thin endometrium by stem cell-based therapies. The human placenta-derived mesenchymal stem cells (HP-MSCs) are emerging alternative sources of MSCs with various advantages. To maximize their retention inside the uterus, we loaded HP-MSCs with cross-linked hyaluronic acid hydrogel (HA hydrogel) to investigate their therapeutic efficacy and possible underlying mechanisms. Methods Ethanol was injected into the mice uterus to establish the endometrium-injured model. The retention time of HP-MSCs and HA hydrogel was detected by in vivo imaging, while the distribution of HP-MSCs was detected by immunofluorescence staining. Functional restoration of the uterus was assessed by testing embryo implantation rates. The endometrial morphological alteration was observed by H&E staining, Masson staining, and immunohistochemistry. In vitro studies were further conducted using EdU, transwell, tube formation, and western blot assays. Results Instilled HP-MSCs with HA hydrogel (HP-MSCs-HA) exhibited a prolonged retention time in mouse uteri than normal HP-MSCs. In vivo studies showed that the HP-MSCs-HA could significantly increase the gland number and endometrial thickness (P < 0.001, P < 0.05), decrease fibrous area (P < 0.0001), and promote the proliferation and angiogenesis of endometrial cells (as indicated by Ki67 and VEGF, P < 0.05, P < 0.05, respectively) in mice injured endometrium. HP-MSCs-HA could also significantly improve the embryo implantation rate (P < 0.01) compared with the ethanol group. Further mechanistic study showed the paracrine effects of HP-MSCs. They could not only promote the proliferation and migration of human endometrial stromal cells via the JNK/Erk1/2-Stat3-VEGF pathway but also facilitate the proliferation of glandular cells via Jak2-Stat5 and c-Fos-VEGF pathway. In turn, the increased VEGF in the endometrium promoted the angiogenesis of endothelial cells. Conclusion Our study suggested the potential therapeutic effects and the underlying mechanisms of HP-MSCs-HA on treating thin endometrium. HA hydrogel could be a preferable delivery method for HP-MSCs, and the strategy represents a promising therapeutic approach against endometrial injury in clinical settings. Graphical abstracthttps://doi.org/10.1186/s13287-022-02717-2Human placenta-derived mesenchymal stem cellsHyaluronic acid hydrogelsThin endometriumEndometrial repairRegeneration mechanisms |
| spellingShingle | Yifeng Lin Shunni Dong Xiaohang Ye Juan Liu Jiaqun Li Yanye Zhang Mixue Tu Siwen Wang Yanyun Ying Ruixue Chen Feixia Wang Feida Ni Jianpeng Chen Binyang Du Dan Zhang Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels Stem Cell Research & Therapy Human placenta-derived mesenchymal stem cells Hyaluronic acid hydrogels Thin endometrium Endometrial repair Regeneration mechanisms |
| title | Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels |
| title_full | Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels |
| title_fullStr | Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels |
| title_full_unstemmed | Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels |
| title_short | Synergistic regenerative therapy of thin endometrium by human placenta-derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels |
| title_sort | synergistic regenerative therapy of thin endometrium by human placenta derived mesenchymal stem cells encapsulated within hyaluronic acid hydrogels |
| topic | Human placenta-derived mesenchymal stem cells Hyaluronic acid hydrogels Thin endometrium Endometrial repair Regeneration mechanisms |
| url | https://doi.org/10.1186/s13287-022-02717-2 |
| work_keys_str_mv | AT yifenglin synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT shunnidong synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT xiaohangye synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT juanliu synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT jiaqunli synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT yanyezhang synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT mixuetu synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT siwenwang synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT yanyunying synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT ruixuechen synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT feixiawang synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT feidani synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT jianpengchen synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT binyangdu synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels AT danzhang synergisticregenerativetherapyofthinendometriumbyhumanplacentaderivedmesenchymalstemcellsencapsulatedwithinhyaluronicacidhydrogels |