Spatial transcriptomics could transform musculoskeletal research

Conventional transcriptomic techniques have revealed much about gene expression at the population and single-cell level—but they overlook one crucial factor: spatial context. In musculoskeletal tissues, where function depends heavily on structure and cellular organization, the loss of spatial information can mean missed opportunities for discovery. Technologies like bulk RNA sequencing and single-cell RNA sequencing fail to capture how neighboring cells interact or how gene activity varies across tissue architecture. These limitations have long hindered efforts to fully understand development, injury, and disease in the musculoskeletal system. Due to these challenges, a deeper exploration using spatially-resolved techniques has become increasingly essential.

In a comprehensive review (DOI: 10.1038/s41413-025-00429-w) published in Bone Research in May 2025, researchers from Hebei Medical University, Xiamen University, and Huazhong University of Science and Technology present an in-depth analysis of spatial transcriptomics and its emerging applications in musculoskeletal research. The team catalogs recent breakthroughs in Spatial Transcriptomics (ST) technologies and outlines how they are being deployed to chart developmental pathways and investigate diseases like arthritis and muscle degeneration. By offering a practical framework for integrating ST tools into research workflows, the authors aim to guide scientists navigating this fast-evolving field.

The review dissects the two main classes of Spatial Transcriptomics (ST) technologies—imaging-based and sequencing-based—comparing their capabilities, trade-offs, and compatibility with various tissue types. Imaging techniques like RNAscope and multiplexed error-robust fluorescence in situ hybridization (MERFISH) deliver pinpoint accuracy for a select set of genes, while sequencing-based methods such as Visium and Stereo-seq provide broad, transcriptome-wide views across larger tissue areas.

Researchers have already leveraged these tools to unravel the molecular choreography of human limb development, trace skeletal stem cell niches, and reveal spatial gene patterns in disorders like rheumatoid arthritis and tendon injuries. In one highlighted case, spatial transcriptomics mapped the intervertebral disc's cellular architecture, identifying progenitor cells responsible for tissue regeneration. In another, it illuminated how scar-forming macrophages and stem cells interact to block muscle repair after trauma. The review also presents a step-by-step guide for selecting appropriate ST platforms based on factors like resolution, cost, species specificity, and research aims—making it a critical resource for scientists entering this space.

Spatial transcriptomics has added an essential dimension to our understanding of musculoskeletal biology. It enables us to pinpoint where genes are active within the intact tissue environment, linking gene function to spatial organization. This level of insight is opening new doors in disease research and therapy development. As we refine the tools and broaden their accessibility, we expect ST to become a foundational technique across orthopedic and regenerative medicine."

Prof. Wei Chen, co-corresponding author and orthopedic surgeon at Hebei Medical University

The ability to map gene expression in space is transforming how we understand and treat musculoskeletal conditions. In developmental biology, spatial transcriptomics helps chart normal growth and detect congenital anomalies. In clinical research, it's revealing the spatial complexity of diseases like osteoarthritis, enabling more precise classification and treatment strategies. Looking ahead, advancements in 3D spatial mapping, spatial multi-omics, and artificial intelligence will further amplify the power of ST. These innovations could lead to personalized therapies, improved biomaterials for tissue repair, and smarter drug targeting—positioning spatial transcriptomics at the heart of the future of musculoskeletal medicine.