Donor-But Not Recipient-Derived Cells Produce Collagen-1 in Chronically Rejected Cardiac Allografts.

Saidou Balam,Sophia Neumayer,Kathrin Schmidbauer,Edward K Geissler,Simone Buchtler,Yvonne Talke,Frederike Winter,Kerstin Renner,Matthias Mack

doi:10.3389/fimmu.2021.816509

Saidou Balam, Sophia Neumayer + Show 7 more

Open Access

https://doi.org/10.3389/fimmu.2021.816509

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Abstract

Fibrosis is a prominent feature of chronic allograft rejection, caused by an excessive production of matrix proteins, including collagen-1. Several cell types produce collagen-1, including mesenchymal fibroblasts and cells of hematopoietic origin. Here, we sought to determine whether tissue-resident donor-derived cells or allograft-infiltrating recipient-derived cells are responsible for allograft fibrosis, and whether hematopoietic cells contribute to collagen production. A fully MHC-mismatched mouse heterotopic heart transplantation model was used, with transient depletion of CD4+ T cells to prevent acute rejection. Collagen-1 was selectively knocked out in recipients or donors. In addition, collagen-1 was specifically deleted in hematopoietic cells. Tissue-resident macrophages were depleted using anti-CSF1R antibody. Allograft fibrosis and inflammation were quantified 20 days post-transplantation. Selective collagen-1 knock-out in recipients or donors showed that tissue-resident cells from donor hearts, but not infiltrating recipient-derived cells, are responsible for production of collagen-1 in allografts. Cell-type-specific knock-out experiments showed that hematopoietic tissue-resident cells in donor hearts substantially contributed to graft fibrosis. Tissue resident macrophages, however, were not responsible for collagen-production, as their deletion worsened allograft fibrosis. Donor-derived cells including those of hematopoietic origin determine allograft fibrosis, making them attractive targets for organ preconditioning to improve long-term transplantation outcomes.

Highlights

Fibrosis is characterized by excessive production of extracellular matrix (ECM) and a major cause of chronic loss of solid graft function [1–4]
In a highly inflammatory model of renal fibrosis, we previously found that hematopoietic cells contribute 30-50% to the production of collagen-1; the contribution of hematopoietic cells was more pronounced at later stages of fibrosis [6]
Mice with a complete deficiency of collagen-1 in hematopoietic cells were generated by crossing C57BL/6 col1a1fl/fl mice with C57BL/6 CD45wt/cre knock-in mice or with Vav1-Cre transgenic mice

Summary

Introduction

Fibrosis is characterized by excessive production of extracellular matrix (ECM) and a major cause of chronic loss of solid graft function [1–4]. Several sources of matrix producing cells have been described in various models of organ fibrosis. Differentiation and activation signals are required to induce matrix production in these cells Their contribution to matrix production is not fully understood and depends on how fibrosis is induced (type of disease) and which organs are affected. Technical limitations impede clear identification of matrix-producing cells, as e.g. fate tracking and imaging depends on specific markers or genes to identify various cell types. It is relevant which matrix proteins (collagens, proteoglycans or glycoporteins) are used to define a matrix-producing cell. In a highly inflammatory model of renal fibrosis (unilateral ureteral obstruction and adenine nephropathy), we previously found that hematopoietic cells contribute 30-50% to the production of collagen-1 (col1a1); the contribution of hematopoietic cells was more pronounced at later stages of fibrosis [6]

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