Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism
Abstract Background Adult hematopoietic stem cells (HSCs) homeostasis is critically important in maintaining lifelong hematopoiesis. However, how adult HSCs orchestrate its homeostasis remains not fully understood. Imprinted gene Dlk1 has been shown to play critical role in mouse embryonic hematopoi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-01-01
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| Series: | Experimental Hematology & Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40164-022-00369-9 |
| _version_ | 1797946026842128384 |
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| author | Deyu Huang Yingli Han Tian Tang Lin Yang Penglei Jiang Wenchang Qian Zhaoru Zhang Xinyue Qian Xin Zeng Pengxu Qian |
| author_facet | Deyu Huang Yingli Han Tian Tang Lin Yang Penglei Jiang Wenchang Qian Zhaoru Zhang Xinyue Qian Xin Zeng Pengxu Qian |
| author_sort | Deyu Huang |
| collection | DOAJ |
| description | Abstract Background Adult hematopoietic stem cells (HSCs) homeostasis is critically important in maintaining lifelong hematopoiesis. However, how adult HSCs orchestrate its homeostasis remains not fully understood. Imprinted gene Dlk1 has been shown to play critical role in mouse embryonic hematopoiesis and in regulation of stem cells, but its physiological roles in adult HSCs are unknown. Methods We performed gene expression analysis of Dlk1, and constructed conditional Dlk1 knockout (KO) mice by crossing Mx1 cre mice with Dlkflox/flox mice. Western blot and quantitative PCR were used to detect Dlk1 KO efficiency. Flow cytometry was performed to investigate the effects of Dlk1 KO on HSCs, progenitors and linage cells in primary mice. Competitive HSCs transplantation and secondary transplantation was used to examine the effects of Dlk1 KO on long-term hematopoietic repopulation potential of HSCs. RNA-Seq and cell metabolism assays was used to determine the underlying mechanisms. Results Dlk1 was highly expressed in adult mice long-term HSCs (LT-HSCs) relative to progenitors and mature lineage cells. Dlk1 KO in adult mice HSCs drove HSCs enter active cell cycle, and expanded phenotypical LT-HSCs, but undermined its long-term hematopoietic repopulation potential. Dlk1 KO resulted in an increase in HSCs’ metabolic activity, including glucose uptake, ribosomal translation, mitochondrial metabolism and ROS production, which impaired HSCs function. Further, Dlk1 KO in adult mice HSCs attenuated Notch signaling, and re-activation of Notch signaling under Dlk1 KO decreased the mitochondrial activity and ROS production, and rescued the changes in frequency and absolute number of HSCs. Scavenging ROS by antioxidant N-acetylcysteine could inhibit mitochondrial metabolic activity, and rescue the changes in HSCs caused by Dlk1 KO. Conclusion Our study showed that Dlk1 played an essential role in maintaining HSC homeostasis, which is realized by governing cell cycle and restricting mitochondrial metabolic activity. |
| first_indexed | 2024-04-10T21:04:23Z |
| format | Article |
| id | doaj.art-886f773e688e4d57a8b0e4b94770e47a |
| institution | Directory Open Access Journal |
| issn | 2162-3619 |
| language | English |
| last_indexed | 2024-04-10T21:04:23Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Experimental Hematology & Oncology |
| spelling | doaj.art-886f773e688e4d57a8b0e4b94770e47a2023-01-22T12:06:34ZengBMCExperimental Hematology & Oncology2162-36192023-01-0112111610.1186/s40164-022-00369-9Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolismDeyu Huang0Yingli Han1Tian Tang2Lin Yang3Penglei Jiang4Wenchang Qian5Zhaoru Zhang6Xinyue Qian7Xin Zeng8Pengxu Qian9Center of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineCenter of Stem Cell and Regenerative Medicine, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of MedicineAbstract Background Adult hematopoietic stem cells (HSCs) homeostasis is critically important in maintaining lifelong hematopoiesis. However, how adult HSCs orchestrate its homeostasis remains not fully understood. Imprinted gene Dlk1 has been shown to play critical role in mouse embryonic hematopoiesis and in regulation of stem cells, but its physiological roles in adult HSCs are unknown. Methods We performed gene expression analysis of Dlk1, and constructed conditional Dlk1 knockout (KO) mice by crossing Mx1 cre mice with Dlkflox/flox mice. Western blot and quantitative PCR were used to detect Dlk1 KO efficiency. Flow cytometry was performed to investigate the effects of Dlk1 KO on HSCs, progenitors and linage cells in primary mice. Competitive HSCs transplantation and secondary transplantation was used to examine the effects of Dlk1 KO on long-term hematopoietic repopulation potential of HSCs. RNA-Seq and cell metabolism assays was used to determine the underlying mechanisms. Results Dlk1 was highly expressed in adult mice long-term HSCs (LT-HSCs) relative to progenitors and mature lineage cells. Dlk1 KO in adult mice HSCs drove HSCs enter active cell cycle, and expanded phenotypical LT-HSCs, but undermined its long-term hematopoietic repopulation potential. Dlk1 KO resulted in an increase in HSCs’ metabolic activity, including glucose uptake, ribosomal translation, mitochondrial metabolism and ROS production, which impaired HSCs function. Further, Dlk1 KO in adult mice HSCs attenuated Notch signaling, and re-activation of Notch signaling under Dlk1 KO decreased the mitochondrial activity and ROS production, and rescued the changes in frequency and absolute number of HSCs. Scavenging ROS by antioxidant N-acetylcysteine could inhibit mitochondrial metabolic activity, and rescue the changes in HSCs caused by Dlk1 KO. Conclusion Our study showed that Dlk1 played an essential role in maintaining HSC homeostasis, which is realized by governing cell cycle and restricting mitochondrial metabolic activity.https://doi.org/10.1186/s40164-022-00369-9Dlk1HSCsMitochondrial metabolismNotchHSC transplantation |
| spellingShingle | Deyu Huang Yingli Han Tian Tang Lin Yang Penglei Jiang Wenchang Qian Zhaoru Zhang Xinyue Qian Xin Zeng Pengxu Qian Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism Experimental Hematology & Oncology Dlk1 HSCs Mitochondrial metabolism Notch HSC transplantation |
| title | Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism |
| title_full | Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism |
| title_fullStr | Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism |
| title_full_unstemmed | Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism |
| title_short | Dlk1 maintains adult mice long-term HSCs by activating Notch signaling to restrict mitochondrial metabolism |
| title_sort | dlk1 maintains adult mice long term hscs by activating notch signaling to restrict mitochondrial metabolism |
| topic | Dlk1 HSCs Mitochondrial metabolism Notch HSC transplantation |
| url | https://doi.org/10.1186/s40164-022-00369-9 |
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