Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model
Mesenchymal stem cell (MSC)-based therapy and novel biomaterials are promising strategies for healing of long bone critical size defects. Interleukin-4 (IL-4) over-expressing MSCs within a gelatin microribbon (µRB) scaffold was previously shown to enhance the bridging of bone within a critical size...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Bioengineering and Biotechnology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fbioe.2021.755964/full |
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| author | Masaya Ueno Masaya Ueno Ning Zhang Hirohito Hirata Danial Barati Takeshi Utsunomiya Huaishuang Shen Tzuhua Lin Masahiro Maruyama Ejun Huang Zhenyu Yao Joy Y. Wu Stefan Zwingenberger Fan Yang Fan Yang Stuart B. Goodman Stuart B. Goodman |
| author_facet | Masaya Ueno Masaya Ueno Ning Zhang Hirohito Hirata Danial Barati Takeshi Utsunomiya Huaishuang Shen Tzuhua Lin Masahiro Maruyama Ejun Huang Zhenyu Yao Joy Y. Wu Stefan Zwingenberger Fan Yang Fan Yang Stuart B. Goodman Stuart B. Goodman |
| author_sort | Masaya Ueno |
| collection | DOAJ |
| description | Mesenchymal stem cell (MSC)-based therapy and novel biomaterials are promising strategies for healing of long bone critical size defects. Interleukin-4 (IL-4) over-expressing MSCs within a gelatin microribbon (µRB) scaffold was previously shown to enhance the bridging of bone within a critical size femoral bone defect in male Balb/c mice. Whether sex differences affect the healing of this bone defect in conjunction with different treatments is unknown. In this study, we generated 2-mm critical-sized femoral diaphyseal bone defects in 10–12-week-old female and male Balb/c mice. Scaffolds without cells and with unmodified MSCs were implanted immediately after the primary surgery that created the bone defect; scaffolds with IL-4 over-expressing MSCs were implanted 3 days after the primary surgery, to avoid the adverse effects of IL-4 on the initial inflammatory phase of fracture healing. Mice were euthanized 6 weeks after the primary surgery and femurs were collected. MicroCT (µCT), histochemical and immunohistochemical analyses were subsequently performed of the defect site. µRB scaffolds with IL-4 over-expressing MSCs enhanced bone healing in both female and male mice. Male mice showed higher measures of bone bridging and increased alkaline phosphatase (ALP) positive areas, total macrophages and M2 macrophages compared with female mice after receiving scaffolds with IL-4 over-expressing MSCs. Female mice showed higher Tartrate-Resistant Acid Phosphatase (TRAP) positive osteoclast numbers compared with male mice. These results demonstrated that sex differences should be considered during the application of MSC-based studies of bone healing. |
| first_indexed | 2024-12-18T02:13:48Z |
| format | Article |
| id | doaj.art-bff4714009c849f2861241bb573887e4 |
| institution | Directory Open Access Journal |
| issn | 2296-4185 |
| language | English |
| last_indexed | 2024-12-18T02:13:48Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Bioengineering and Biotechnology |
| spelling | doaj.art-bff4714009c849f2861241bb573887e42022-12-21T21:24:26ZengFrontiers Media S.A.Frontiers in Bioengineering and Biotechnology2296-41852021-10-01910.3389/fbioe.2021.755964755964Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect ModelMasaya Ueno0Masaya Ueno1Ning Zhang2Hirohito Hirata3Danial Barati4Takeshi Utsunomiya5Huaishuang Shen6Tzuhua Lin7Masahiro Maruyama8Ejun Huang9Zhenyu Yao10Joy Y. Wu11Stefan Zwingenberger12Fan Yang13Fan Yang14Stuart B. Goodman15Stuart B. Goodman16Department of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Faculty of Medicine, Saga University, Saga, JapanDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Medicine, Stanford University, Stanford, CA, United StatesUniversity Center for Orthopaedics, Traumatology, and Plastic Surgery, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, GermanyDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Bioengineering, Stanford University, Stanford, CA, United StatesDepartment of Orthopaedic Surgery, Stanford University, Stanford, CA, United StatesDepartment of Bioengineering, Stanford University, Stanford, CA, United StatesMesenchymal stem cell (MSC)-based therapy and novel biomaterials are promising strategies for healing of long bone critical size defects. Interleukin-4 (IL-4) over-expressing MSCs within a gelatin microribbon (µRB) scaffold was previously shown to enhance the bridging of bone within a critical size femoral bone defect in male Balb/c mice. Whether sex differences affect the healing of this bone defect in conjunction with different treatments is unknown. In this study, we generated 2-mm critical-sized femoral diaphyseal bone defects in 10–12-week-old female and male Balb/c mice. Scaffolds without cells and with unmodified MSCs were implanted immediately after the primary surgery that created the bone defect; scaffolds with IL-4 over-expressing MSCs were implanted 3 days after the primary surgery, to avoid the adverse effects of IL-4 on the initial inflammatory phase of fracture healing. Mice were euthanized 6 weeks after the primary surgery and femurs were collected. MicroCT (µCT), histochemical and immunohistochemical analyses were subsequently performed of the defect site. µRB scaffolds with IL-4 over-expressing MSCs enhanced bone healing in both female and male mice. Male mice showed higher measures of bone bridging and increased alkaline phosphatase (ALP) positive areas, total macrophages and M2 macrophages compared with female mice after receiving scaffolds with IL-4 over-expressing MSCs. Female mice showed higher Tartrate-Resistant Acid Phosphatase (TRAP) positive osteoclast numbers compared with male mice. These results demonstrated that sex differences should be considered during the application of MSC-based studies of bone healing.https://www.frontiersin.org/articles/10.3389/fbioe.2021.755964/fullsex differencesbone healingmesenchymal stem cellmicroribbon hydrogelinterleukin-4 |
| spellingShingle | Masaya Ueno Masaya Ueno Ning Zhang Hirohito Hirata Danial Barati Takeshi Utsunomiya Huaishuang Shen Tzuhua Lin Masahiro Maruyama Ejun Huang Zhenyu Yao Joy Y. Wu Stefan Zwingenberger Fan Yang Fan Yang Stuart B. Goodman Stuart B. Goodman Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model Frontiers in Bioengineering and Biotechnology sex differences bone healing mesenchymal stem cell microribbon hydrogel interleukin-4 |
| title | Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model |
| title_full | Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model |
| title_fullStr | Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model |
| title_full_unstemmed | Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model |
| title_short | Sex Differences in Mesenchymal Stem Cell Therapy With Gelatin-Based Microribbon Hydrogels in a Murine Long Bone Critical-Size Defect Model |
| title_sort | sex differences in mesenchymal stem cell therapy with gelatin based microribbon hydrogels in a murine long bone critical size defect model |
| topic | sex differences bone healing mesenchymal stem cell microribbon hydrogel interleukin-4 |
| url | https://www.frontiersin.org/articles/10.3389/fbioe.2021.755964/full |
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