Recently, an article titled "Mgp High-Expressing MSCs Orchestrate the Osteoimmune Microenvironment of Collagen/Nanohydroxyapatite-Mediated Bone Regeneration" was published in the journal Advanced Science (IF=17.521). This research, powered by Novogene's cutting-edge single-cell and spatial multi-omics technologies, sheds new light on the intricate cellular mechanisms underlying bone regeneration mediated by collagen/nanohydroxyapatite (Col/nHA) implants.
Introduction
Regenerating bone tissue lost due to fractures, osteoporosis, or surgery remains a significant challenge in medicine. While advancements have been made, the intricate cellular and molecular processes orchestrating bone healing are not fully understood. At the center of this intricate symphony stand two key players: Stem cells and Biomaterials.
Stem cells, with their remarkable potential to transform into specialized cell types, hold immense promise. Researchers have successfully used various types of stem cells, such as mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs), for bone tissue engineering and bone regeneration. Among these, mesenchymal stem cells (MSCs) are particularly attractive due to their abundance in adult tissues and their ability to differentiate into bone-forming cells (osteoblasts) when presented with the right environment (1).
Biomaterials, on the other hand, act as the stage for this cellular performance. These engineered materials, like collagen/nanohydroxyapatite (Col/nHA) scaffolds, mimic the natural bone extracellular matrix. They provide crucial structural support, promote cell adhesion and growth, and some can even release growth factors that further stimulate bone regeneration (2,3).
However, the success of this bone repair "concert" hinges on the dynamic interplay between stem cells and biomaterials. Understanding how stem cells respond to biomaterials across space and time is critical for optimizing these therapeutic strategies.
Overview
This study delves into this crucial interaction. By leveraging Novogene's cutting-edge single-cell and spatial multi-omics technologies, the researchers dissect the bone immune microenvironment surrounding Col/nHA implants in mouse models (4). Their single-cell analysis unveils the impact of these biomaterials on the spatiotemporal expression patterns of MSCs, offering valuable insights for improving the efficacy of bone repair materials (4).
Study Design
The researchers utilized single-cell RNA sequencing (scRNA-seq) to profile the transcriptomes of individual cells within the microenvironment around the implanted biomaterials in mouse models.
Further, spatial transcriptomics techniques were utilized to determine the spatial organization and localization of different cell types and gene expression patterns within the microenvironment surrounding the implanted biomaterials.
Key Findings
Through the integrated analysis of Novogene's advanced single-cell and spatial multi-omics technologies, researchers comprehended the cellular heterogeneity of MSCs around the bone defect regions post-implantation of biomaterial (4)
- Using scRNA-seq they subcategorized the MSCs into 9 major subsets based on the reporter marker gene.
- Gene ontology (GO) enrichment analysis helped in deciphering the distinct functions of each subset.
- A subpopulation of MSCs termed OPs2 (or MgphiMSCs) highly expressed the matrix Gla protein (MGP) gene.
- Higher MGP gene expression levels were observed in regions with the bioactive biomaterials as compared to regions without bioactive materials.
- The OPs2/ MgphiMSCs exhibited spatial localization preferences in the early stage of bone defect repair, suggesting a role in initiating the regeneration process.
- The Mgp-high MSCs also promoted angiogenesis and osteogenesis, contributing to the formation of new blood vessels and bone tissue. New blood vessels help in delivering oxygen and nutrients to the healing bone.
- GO enrichment and KEGG pathway analysis suggested that MgphiMSCs enhance bone regeneration through the PI3K Akt signaling pathway.
- CellChat database showed that MgphiMSCs exhibited crosstalk with multiple immune cells via the secreted phosphoprotein 1 (SPP1) signaling pathway.
- Mgp hiMSCs also inhibit M1 polarization and differentiation of macrophages through Mdk / Lrp1 ligand receptor pairs.
Discussion
This study sheds light on the intricate interplay between the MSC subset OPs2/ MgphiMSCs and the bone regeneration process mediated by collagen/nanohydroxyapatite (Col/nHA) biomaterials. The researchers observed a preferential localization of Mgp high-expressing MSCs (MgphiMSCs) at the site of bone tissue damage where the Col/nHA biomaterial was implanted. This spatial distribution pattern, coupled with the early presence of MgphiSCs at the implanted region, suggests their potential involvement in initiating the regenerative process.
Notably, the MgphiMSCs exhibited a remarkable ability to promote angiogenesis and osteogenesis, two crucial processes for the formation of new blood vessels and bone tissue, respectively (5). This finding highlights the potential role of MgphiMSCs in facilitating the regeneration of vascularized bone tissue, a critical aspect of successful bone repair. Furthermore, the study revealed a fascinating interaction between MgphiMSCs and macrophages, a key immune cell type involved in the bone regeneration process. The MgphiMSCs were found to regulate the polarization and osteoclastic differentiation of macrophages through the Mdk/Lrp1 ligand-receptor pair. By inhibiting the pro-inflammatory M1 polarization of macrophages and promoting the anti-inflammatory M2 polarization, MgphiMSCs create a microenvironment that favors new bone formation.
This intricate interplay between MgphiMSCs and the immune system, particularly macrophages, highlights the complex cellular dynamics that govern the bone regeneration process. Understanding these interactions could provide valuable insights into modulating the osteoimmune microenvironment to enhance the efficacy of biomaterial-mediated bone repair strategies.
Implications and Future Directions
This study represents a paradigm shift in our understanding of bone regeneration.
The high-resolution analysis using scRNA-seq revealed a previously unknown subpopulation of MSCs with high expression of the gene Matrix Gla Protein (Mgp), aptly named Mgp high-expressing MSCs (MgphiMSCs). Spatial transcriptomics further revealed the "cellular neighborhoods" of MgphiMSCs, providing valuable insights into potential interactions with their neighbors.
Combined single-cell and spatial transcriptomics enable researchers to understand how MgphiMSCs were distributed relative to other cell types and the biomaterial itself. Furthermore, the ability to map the spatial organization of the bone regeneration microenvironment could guide the design of biomimetic scaffolds that recapitulate the native cellular and molecular architecture, potentially improving the efficacy of bone graft substitutes.
Powered by Novogene's high-resolution single-cell RNA-seq analysis, this study reveals the pivotal role of MgphiMSCs and paves the way for developing innovative therapeutic strategies.
References
1.Iaquinta, M. R., Mazzoni, E., Bononi, I., Rotondo, J. C., Mazziotta, C., Montesi, M., Sprio, S., Tampieri, A., Tognon, M., & Martini, F. (2019). Adult Stem Cells for Bone Regeneration and Repair. In Frontiers in Cell and Developmental Biology (Vol. 7). doi:10.3389/fcell.2019.00268
2.Winkler, T., Sass, F. A., Duda, G. N., & Schmidt-Bleek, K. (2018). A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: The unsolved challenge. In Bone and Joint Research (Vol. 7, Issue 3). doi:10.1302/20463758.73.BJR-2017-0270.R1
3.Yu, X., Tang, X., Gohil, S. V., & Laurencin, C. T. (2015). Biomaterials for Bone Regenerative Engineering. In Advanced Healthcare Materials (Vol. 4, Issue 9). doi:10.1002/adhm.201400760
4.Wan Z, Bai X, Wang X, et al. Mgp High-Expressing MSCs Orchestrate the Osteoimmune Microenvironment of Collagen/Nanohydroxyapatite-Mediated Bone Regeneration. Adv Sci (Weinh). Published online April 8, 2024. doi:10.1002/advs.202308986
5.Stegen, S., van Gastel, N., & Carmeliet, G. (2015). Bringing new life to damaged bone: The importance of angiogenesis in bone repair and regeneration. Bone, 70. doi:10.1016/j.bone.2014.09.017
6.He, J., Chen, G., Liu, M., Xu, Z., Chen, H., Yang, L., & Lv, Y. (2020). Scaffold strategies for modulating immune microenvironment during bone regeneration. In Materials Science and Engineering C (Vol.108). doi:10.1016/j.msec.2019.110411
