Type-I collagen produced by distinct fibroblast lineages reveals specific function during embryogenesis and Osteogenesis Imperfecta

Yang Chen,Kathleen M Mcandrews,Hikaru Sugimoto,Sujuan Yang,Catherine G Ambrose,Raghu Kalluri,Sara Lovisa

doi:10.1038/s41467-021-27563-3

Abstract

Type I collagen (Col1) is the most abundant protein in mammals. Col1 contributes to 90% of the total organic component of bone matrix. However, the precise cellular origin and functional contribution of Col1 in embryogenesis and bone formation remain unknown. Single-cell RNA-sequencing analysis identifies Fap+ cells and Fsp1+ cells as the major contributors of Col1 in the bone. We generate transgenic mouse models to genetically delete Col1 in various cell lineages. Complete, whole-body Col1 deletion leads to failed gastrulation and early embryonic lethality. Specific Col1 deletion in Fap+ cells causes severe skeletal defects, with hemorrhage, edema, and prenatal lethality. Specific Col1 deletion in Fsp1+ cells results in Osteogenesis Imperfecta-like phenotypes in adult mice, with spontaneous fractures and compromised bone healing. This study demonstrates specific contributions of mesenchymal cell lineages to Col1 production in organogenesis, skeletal development, and bone formation/repair, with potential insights into cell-based therapy for patients with Osteogenesis Imperfecta.

Highlights

Type I collagen (Col1) is the most abundant protein in mammals
We determined that Col1a1 is highly expressed by MSCdescendent osteolineage cells (OLCs) and fibroblasts (Fig. 1d)
We simultaneously examined the expression of several genes encoding common fibroblast/mesenchymal markers, such as Fap, S100a4, and Acta[2], among the cell populations of bone and bone marrow

Summary

Introduction

Type I collagen (Col1) is the most abundant protein in mammals. Col[1] contributes to 90% of the total organic component of bone matrix. This study demonstrates specific contributions of mesenchymal cell lineages to Col[1] production in organogenesis, skeletal development, and bone formation/ repair, with potential insights into cell-based therapy for patients with Osteogenesis Imperfecta. Recent studies, using singlecell RNA sequencing analysis (sc-RNA-seq) and other techniques, highlighted the distinct features and potential functions of various osteogenic cell subpopulations in the bone and bone marrow, shedding some light on the potential mechanisms driving bone homeostasis and repair[26,27,28] In this present study, we analyzed sc-RNA-seq dataset on bone and bone marrow stroma of healthy mice[27], and identified the expression of Col1a1 gene dominantly in Fap+ (fibroblast activation protein; encoded by Fap) mesenchymal cells, as well as S100a4+ ( known as fibroblastspecific protein 1, Fsp[1]; encoded by S100a4) mesenchymal cells. The Col1a1loxP/loxP mouse strain was crossed with multiple Cre recombinase mouse strains including CMV-Cre, Fap-Cre, Fsp[1] (S100a4)-Cre, αSMA (Acta2)-Cre, and Cdh5-Cre strains These mice revealed distinct phenotypes due to Cre recombinase-driven Col[1] deletion in targeted cell lineages. This study provides comprehensive investigation of the functional roles of Col[1] produced by various cell lineages in organogenesis, osteogenesis, and bone-related diseases

Methods

Results

Conclusion