In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras
Generation of bone marrow (BM) from embryonic stem cells (ESCs) promises to accelerate the development of future cell therapies for life-threatening disorders. However, such approach is limited by technical challenges to produce a mixture of functional BM progenitor cells able to replace all hematop...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/74018 |
| _version_ | 1811181877723136000 |
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| author | Bingqiang Wen Guolun Wang Enhong Li Olena A Kolesnichenko Zhaowei Tu Senad Divanovic Tanya V Kalin Vladimir V Kalinichenko |
| author_facet | Bingqiang Wen Guolun Wang Enhong Li Olena A Kolesnichenko Zhaowei Tu Senad Divanovic Tanya V Kalin Vladimir V Kalinichenko |
| author_sort | Bingqiang Wen |
| collection | DOAJ |
| description | Generation of bone marrow (BM) from embryonic stem cells (ESCs) promises to accelerate the development of future cell therapies for life-threatening disorders. However, such approach is limited by technical challenges to produce a mixture of functional BM progenitor cells able to replace all hematopoietic cell lineages. Herein, we used blastocyst complementation to simultaneously produce BM cell lineages from mouse ESCs in a rat. Based on fluorescence-activated cell sorting analysis and single-cell RNA sequencing, mouse ESCs differentiated into multiple hematopoietic and stromal cell types that were indistinguishable from normal mouse BM cells based on gene expression signatures and cell surface markers. Receptor–ligand interactions identified Cxcl12-Cxcr4, Lama2-Itga6, App-Itga6, Comp-Cd47, Col1a1-Cd44, and App-Il18rap as major signaling pathways between hematopoietic progenitors and stromal cells. Multiple hematopoietic progenitors, including hematopoietic stem cells (HSCs) in mouse–rat chimeras derived more efficiently from mouse ESCs, whereas chondrocytes predominantly derived from rat cells. In the dorsal aorta and fetal liver of mouse–rat chimeras, mouse HSCs emerged and expanded faster compared to endogenous rat cells. Sequential BM transplantation of ESC-derived cells from mouse–rat chimeras rescued lethally irradiated syngeneic mice and demonstrated long-term reconstitution potential of donor HSCs. Altogether, a fully functional BM was generated from mouse ESCs using rat embryos as ‘bioreactors’. |
| first_indexed | 2024-04-11T09:23:11Z |
| format | Article |
| id | doaj.art-0429308501c1400daa3a7f22a3d735db |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:23:11Z |
| publishDate | 2022-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0429308501c1400daa3a7f22a3d735db2022-12-22T04:32:05ZengeLife Sciences Publications LtdeLife2050-084X2022-09-011110.7554/eLife.74018In vivo generation of bone marrow from embryonic stem cells in interspecies chimerasBingqiang Wen0https://orcid.org/0000-0001-8827-4820Guolun Wang1Enhong Li2Olena A Kolesnichenko3Zhaowei Tu4Senad Divanovic5https://orcid.org/0000-0001-7538-0499Tanya V Kalin6Vladimir V Kalinichenko7https://orcid.org/0000-0003-3438-2660Center for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United StatesCenter for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United StatesCenter for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United StatesCenter for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United StatesDivision of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United StatesDivision of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States; Department of Pediatrics, College of Medicine of the University of Cincinnati, Cincinnati, United StatesDepartment of Pediatrics, College of Medicine of the University of Cincinnati, Cincinnati, United States; Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United StatesCenter for Lung Regenerative Medicine, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States; Department of Pediatrics, College of Medicine of the University of Cincinnati, Cincinnati, United States; Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States; Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United StatesGeneration of bone marrow (BM) from embryonic stem cells (ESCs) promises to accelerate the development of future cell therapies for life-threatening disorders. However, such approach is limited by technical challenges to produce a mixture of functional BM progenitor cells able to replace all hematopoietic cell lineages. Herein, we used blastocyst complementation to simultaneously produce BM cell lineages from mouse ESCs in a rat. Based on fluorescence-activated cell sorting analysis and single-cell RNA sequencing, mouse ESCs differentiated into multiple hematopoietic and stromal cell types that were indistinguishable from normal mouse BM cells based on gene expression signatures and cell surface markers. Receptor–ligand interactions identified Cxcl12-Cxcr4, Lama2-Itga6, App-Itga6, Comp-Cd47, Col1a1-Cd44, and App-Il18rap as major signaling pathways between hematopoietic progenitors and stromal cells. Multiple hematopoietic progenitors, including hematopoietic stem cells (HSCs) in mouse–rat chimeras derived more efficiently from mouse ESCs, whereas chondrocytes predominantly derived from rat cells. In the dorsal aorta and fetal liver of mouse–rat chimeras, mouse HSCs emerged and expanded faster compared to endogenous rat cells. Sequential BM transplantation of ESC-derived cells from mouse–rat chimeras rescued lethally irradiated syngeneic mice and demonstrated long-term reconstitution potential of donor HSCs. Altogether, a fully functional BM was generated from mouse ESCs using rat embryos as ‘bioreactors’.https://elifesciences.org/articles/74018interspecies chimerasbone marrowirradiationmiceratsblastocyst complementation |
| spellingShingle | Bingqiang Wen Guolun Wang Enhong Li Olena A Kolesnichenko Zhaowei Tu Senad Divanovic Tanya V Kalin Vladimir V Kalinichenko In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras eLife interspecies chimeras bone marrow irradiation mice rats blastocyst complementation |
| title | In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras |
| title_full | In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras |
| title_fullStr | In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras |
| title_full_unstemmed | In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras |
| title_short | In vivo generation of bone marrow from embryonic stem cells in interspecies chimeras |
| title_sort | in vivo generation of bone marrow from embryonic stem cells in interspecies chimeras |
| topic | interspecies chimeras bone marrow irradiation mice rats blastocyst complementation |
| url | https://elifesciences.org/articles/74018 |
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