Linking transcriptome and morphology in bone cells at cellular resolution with generative AI

Abstract Recent advancements in deep learning (DL) have revolutionized the capability of artificial intelligence (AI) by enabling the analysis of large-scale, complex datasets that are difficult for humans to interpret. However, large amounts of high-quality data are required to train such generative AI models successfully. With the rapid commercialization of single-cell sequencing and spatial transcriptomics platforms, the field is increasingly producing large-scale datasets such as histological images, single-cell molecular data, and spatial transcriptomic data. These molecular and morphological datasets parallel the multimodal text and image data used to train highly successful generative AI models for natural language processing and computer vision. Thus, these emerging data types offer great potential to train generative AI models that uncover intricate biological processes of bone cells at a cellular level. In this Perspective, we summarize the progress and prospects of generative AI applied to these datasets and their potential applications to bone research. In particular, we highlight three AI applications: predicting cell differentiation dynamics, linking molecular and morphological features, and predicting cellular responses to perturbations. To make generative AI models beneficial for bone research, important issues, such as technical biases in bone single-cell datasets, lack of profiling of important bone cell types, and lack of spatial information, need to be addressed. Realizing the potential of generative AI for bone biology will also likely require generating large-scale, high-quality cellular-resolution spatial transcriptomics datasets, improving the sensitivity of current spatial transcriptomics datasets, and thorough experimental validation of model predictions.