Mitochondrial clone tracing within spatially intact human tissues.

Area of Science:

• Cell Biology
• Genomics
• Biotechnology

Background:

• Understanding tissue development and evolution requires lineage tracing within intact tissues.
• Current lineage tracing tools are incompatible with spatial omics, limiting spatial context.
• Endogenous mutations are preferable for lineage tracing in human tissues.

Purpose of the Study:

• To develop a spatially-resolved lineage tracing technology integrating gene expression profiling with mitochondrial mutation identification.
• To enable lineage tracing in human tissues using endogenous mutations.
• To characterize cell type composition and spatial configuration within identified clones.

Main Methods:

• SUMMIT (Spatially Unveiling Mitochondrial Mutations In Tissues) integrates gene expression profiling with mitochondrial mutation-based clone identification.
• A statistical framework addresses cell type mixing within spatial spots, assigning variants to subpopulations.
• Information pooling across neighboring spots enhances power for detecting spatially localized clones.

Main Results:

• SUMMIT was validated in a controlled mouse tumor model and applied to human tissues (Barrett's esophagus, gastric cardia, small bowel, colorectal cancer).
• Distinguished between global mutations and mutations marking locally restricted clones.
• Characterized cell type composition and spatial configuration within clones using coupled transcriptomic data.

Conclusions:

• SUMMIT provides a novel framework for spatially-resolved lineage tracing in human tissues.
• This technology integrates endogenous mitochondrial mutations with spatial transcriptomics.
• Enables detailed characterization of spatially-defined clonal evolution in various human tissues.