Mesenchymal stromal cells alleviate pulmonary arterial hypertension by suppressing pulmonary arterial adventitial fibroblast activation and extracellular matrix remodeling via the SOCS3/STAT3 pathway

Abstract

Background: Pulmonary arterial hypertension (PAH) is a fatal condition characterized by progressive vascular remodeling in the pulmonary arteries, eventually leading to right heart failure and death. Dysregulated extracellular matrix (ECM) remodeling is central to PAH pathogenesis and represents a potential therapeutic target. Mesenchymal stromal cells (MSCs) have shown promise in preclinical studies; however, the optimal therapeutic window, dosing frequency, and mechanistic basis for their regulation of vascular ECM remain unclear. Methods: We employed a monocrotaline (MCT)-induced rat model of PAH to evaluate different MSC treatment regimens, including early administration (day 1 post-MCT), delayed administration (days 7 and 14), and repeated dosing (days 1 and 11). Additionally, we combined in vivo and in vitro approaches to investigate how MSCs modulate the activation of pulmonary arterial adventitial fibroblasts (PAAFs) and influence ECM remodeling. Results: Biodistribution studies indicated that MSC retention in lung tissue peaked within 24 h and gradually declined by day 21. A single early dose of MSCs (on day 1) significantly ameliorated PAH progression, increasing the 28-day survival rate, reducing right ventricular systolic pressure (RVSP), improving right ventricular function, and attenuating small pulmonary vascular remodeling, including reductions in medial thickening, excessive muscularization, and collagen deposition. Repeated MSC administration did not provide additive therapeutic benefit. Both in animal models and cell cultures, MSCs effectively suppressed PAAF activation and reduced ECM protein production. This anti-fibrotic effect was mediated, at least in part, via the pathway involving the upregulation of SOCS3 and consequent inhibition of STAT3 phosphorylation. Conclusion: Our findings underscore the importance of early intervention in the PAH disease course for MSC-based therapy. MSCs attenuate vascular remodeling and disease progression, possibly through the SOCS3/STAT3 signaling pathway, by targeting PAAF activation and ECM dysregulation. These results offer a novel mechanistic foundation for MSC treatment in PAH.

1. Introduction

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. It is characterized by increased pulmonary vascular resistance and elevated pulmonary arterial pressure, ultimately leading to right ventricular (RV) failure and death [1, 2]. The core pathology involves perivascular inflammation and fibrosis mediated by multiple immune cells. These cells release various cytokines that cause endothelial injury, fibroblast activation, and smooth muscle cell (SMC) hyperproliferation, collectively driving vascular remodeling [3, 4]. Current treatments primarily target endothelial dysfunction and SMC-mediated vasoconstriction through pathways such as nitric oxide, endothelin-1, and prostacyclin [5]. However, therapeutic efficacy remains limited, and long-term survival is poor. The five-year survival rate remains around 60% even with combination therapy [6].

Mesenchymal stromal cells (MSCs) are stem cells with broad immunoregulatory functions. They can be sourced from various tissues and have shown potential in controlling fibroblast activation. They have been applied in multiple fibrotic diseases, including those of the liver, kidney, and lungs [7–9]. In preclinical PAH studies, MSC administration has been shown to improve pulmonary vascular remodeling [10]. This is achieved by suppressing inflammation mediated by macrophages and lymphocytes, promoting endothelial repair, and reducing SMC overgrowth [10]. Nevertheless, their clinical application remains limited, largely due to an incomplete understanding of their mechanisms of action.