Human Diseased Articular Cartilage Contains a Mesenchymal Stem Cell-Like Population of Chondroprogenitors with Strong Immunomodulatory Responses.

Paola De Luca,Laura De Girolamo,Dimitrios Kouroupis,Carlotta Perucca-Orfei,Marco Viganò,Diego Correa,Lee Kaplan,Luigi Zagra,Alessandra Colombini

doi:10.3390/jcm8040423

Abstract

Background: osteoarthritic human articular cartilage (AC)-derived cartilage cells (CCs) with same-donor bone marrow (BMSCs) and adipose tissue (ASCs)-derived mesenchymal stem cells were compared, in terms of stemness features, and secretory and immunomodulatory responses to inflammation. Methods: proteoglycan 4 (PRG4) presence was evaluated in AC and CCs. MSCs and CCs (n = 8) were cultured (P1 to P4) and characterized for clonogenicity, nanog homeobox (NANOG), and POU class 5 homeobox 1 (POU5F1) expression, immunotypification, and tri-lineage differentiation. Their basal and interleukin-1β (IL-1β)-stimulated expression of matrix metalloproteases (MMPs), tissue inhibitors (TIMPs), release of growth factors, and cytokines were analyzed, along with the immunomodulatory ability of CCs. Results: PRG4 was mainly expressed in the intact AC surface, whereas shifted to the intermediate zone in damaged cartilage and increased its expression in CCs upon culture. All cells exhibited a similar phenotype and stemness maintenance over passages. CCs showed highest chondrogenic ability, no adipogenic potential, a superior basal secretion of growth factors and cytokines, the latter further increased after inflammatory stimulation, and an immunomodulatory behavior. All stimulated cells shared an increased MMP expression without a corresponding TIMP production. Conclusion: based on the observed features, CCs obtained from pathological joints may constitute a potential tissue-specific therapeutic target or agent to improve damaged cartilage healing, especially damage caused by inflammatory/immune mediated conditions.

Highlights

The study of resident adult stem cells and progenitors in tissues with limited self-renewal ability, such as articular cartilage (AC), constitutes a partially explored research field with constant growing interest [1]
In the damaged AC sections, the tissue structure appeared non-homogeneous, exemplified by a distorted superficial zone, with proteoglycan 4 (PRG4) expression randomly distributed in the intermediate zone within cartilage cells (CCs) (Figure 1A)
This study confirmed the presence of active chondrogenic progenitors within human cartilage obtained from OA patients, revealed their active and enhanced secretory responses to inflammation when compared with mesenchymal stem cells (MSCs), and showed their immunomodulatory effects that may be harnessed under novel therapeutic schemes

Summary

Introduction

The study of resident adult stem cells and progenitors in tissues with limited self-renewal ability, such as articular cartilage (AC), constitutes a partially explored research field with constant growing interest [1]. Those specific cells can become a target or be part of regenerative-based novel treatments for AC damage. AC contains a mixed population of cartilage cells (CCs) composed by differentiated matrix-embedded chondrocytes and a pool of resident cartilage-derived stem/progenitor cells (CSPCs) The latter cell population presents a stem-like immuno-phenotype, with chondrogenic potential and the ability to respond to injury with an increased migratory behavior.

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