Harnessing matrix stiffness to engineer a bone marrow niche for hematopoietic stem cell rejuvenation

Xiaoying Zhang; Dandan Cao; Liting Xu; Yanhua Xu; Zehua Gao; Yuanzhong Pan; Ming Jiang; Yuhui Wei; Lihua Wang; Yue Liao; Qigang Wang; Lei Yang; Xiaocui Xu; Yawei Gao; Shaorong Gao; Jing Wang; Rui Yue

doi:10.1016/j.stem.2023.03.005

Harnessing matrix stiffness to engineer a bone marrow niche for hematopoietic stem cell rejuvenation

Cell Stem Cell. 2023 Apr 6;30(4):378-395.e8. doi: 10.1016/j.stem.2023.03.005.

Authors

Xiaoying Zhang¹, Dandan Cao¹, Liting Xu¹, Yanhua Xu², Zehua Gao³, Yuanzhong Pan³, Ming Jiang³, Yuhui Wei⁴, Lihua Wang⁴, Yue Liao⁵, Qigang Wang⁵, Lei Yang⁶, Xiaocui Xu⁶, Yawei Gao⁷, Shaorong Gao⁶, Jing Wang³, Rui Yue⁸

Affiliations

¹ Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
² Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
³ The State Key Laboratory of Bioreactor Engineering, Engineering Research Center for Biomedical Materials of Ministry of Education, East China University of Science and Technology, Shanghai 200237, China.
⁴ The Interdisciplinary Research Center, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, China.
⁵ School of Chemical Science and Engineering, Tongji University, Shanghai 200092, China.
⁶ Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
⁷ Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China.
⁸ Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, China. Electronic address: ryue@tongji.edu.cn.

PMID: 37028404
DOI: 10.1016/j.stem.2023.03.005

Abstract

Hematopoietic stem cell (HSC) self-renewal and aging are tightly regulated by paracrine factors from the bone marrow niche. However, whether HSC rejuvenation could be achieved by engineering a bone marrow niche ex vivo remains unknown. Here, we show that matrix stiffness fine-tunes HSC niche factor expression by bone marrow stromal cells (BMSCs). Increased stiffness activates Yap/Taz signaling to promote BMSC expansion upon 2D culture, which is largely reversed by 3D culture in soft gelatin methacrylate hydrogels. Notably, 3D co-culture with BMSCs promotes HSC maintenance and lymphopoiesis, reverses aging hallmarks of HSCs, and restores their long-term multilineage reconstitution capacity. In situ atomic force microscopy analysis reveals that mouse bone marrow stiffens with age, which correlates with a compromised HSC niche. Taken together, this study highlights the biomechanical regulation of the HSC niche by BMSCs, which could be harnessed to engineer a soft bone marrow niche for HSC rejuvenation.

Keywords: aging; bone marrow stromal cell; hematopoietic stem cell; matrix; niche; rejuvenation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow* / metabolism
Coculture Techniques
Hematopoietic Stem Cells / metabolism
Mesenchymal Stem Cells* / metabolism
Mice
Rejuvenation
Stem Cell Niche