Three-dimensional quantitative tissue clearing reveals differences in osteovascular niche of aged and young human mesenchymal stromal cells
Human bone marrow mesenchymal stromal/stem cells (BM-MSCs) are widely used in clinical trials and tissue engineering, yet their native microenvironment remains poorly understood. Here we introduce a tissue-clearing protocol, DeepBone, for human bones and integrate it with simultaneous mRNA and protein detection. Using this protocol, we spatially map BM-MSCs relative to key bone microenvironment components, including human blood capillaries, adipocytes, sinusoids and bony trabeculae. Quantitative analysis reveals that the native microenvironment of human BM-MSCs in young bone is enriched in vasculature, sinusoids, bone matrix and adipocytes. In contrast, in aged bone, BM-MSCs show no preferential association with bone or adipocytes. Proliferative BM-MSCs are predominantly found along blood vessels. Moreover, we identify a specialized microenvironment for BM-MSCs in young bone, characterized by sinusoids coiled around trabeculae and enriched by R-type vessels. These findings provide insights into the native niches of BM-MSCs, offering a foundation for the development of tissue engineering strategies that mimic their physiological context.
Authors
- Giovanni Volpe (ORCID: https://orcid.org/0000-0001-5057-1846)
- Andrei S. Chagin (ORCID: https://orcid.org/0000-0002-2696-5850)
- Lars Sävendahl (ORCID: https://orcid.org/0000-0003-1067-4976)
- Dana Trompet (ORCID: https://orcid.org/0000-0001-9472-6184)
- Emiliano Gómez Ruiz
- Misty Shuo Zhang
- Nelson Tsz Long Chu
- Mats Brittberg (ORCID: https://orcid.org/0000-0003-2399-5314)
- Björn Barenius (ORCID: https://orcid.org/0000-0002-7941-450X)
- Ostap A. Dregval (ORCID: https://orcid.org/0000-0002-9939-6492)
- Inger Gjertsson (ORCID: https://orcid.org/0000-0002-9301-4844)
- Zhong Li (ORCID: https://orcid.org/0000-0002-5345-3359)
- Ralf H. Adams
- Xin Liu (ORCID: https://orcid.org/0009-0003-4063-7903)
- Emil Kriukov
- Joana B. Pereira (ORCID: https://orcid.org/0000-0002-4604-2711)
- Yu-Wei Chang
- Claes Ohlsson
- Lei Li
- Xin Tian
Institutions
- Massachusetts Eye and Ear Infirmary (US)
- Karolinska University Hospital (SE)
- Harvard University (US)
- Science for Life Laboratory (SE)
- Sahlgrenska University Hospital (SE)
- Karolinska Institutet (SE)
- Max Planck Institute for Molecular Biomedicine (DE)
- First Affiliated Hospital Zhejiang University (CN)
- Smith-Kettlewell Eye Research Institute (US)
- University of Gothenburg (SE)
Publication Details
- Journal
- Nature Biomedical Engineering
- Published
- 2026-04-17
- DOI
- https://doi.org/10.1038/s41551-026-01645-3
- Primary Topic
- Mesenchymal stem cell research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- IngaBritt och Arne Lundbergs Forskningsstiftelse
- Vetenskapsrådet
- Novo Nordisk Fonden