Successful Human Umbilical Cord Mesenchymal Stem Cell-Derived Treatment of Severe Pulmonary Arterial Hypertension: In Vivo Effects and First-In-Human Application

Background: Mesenchymal stem cells (MSCs) are promising therapeutic agents for heart–lung tissue regeneration. Human umbilical cord (HUC) MSC-derived therapies remain unexplored in pulmonary arterial hypertension (PAH) phase 1/2 studies.

Method: Athymic rats were separated into three groups: control normoxia (ConNx), Sugen normoxia (SuNx + HUVEC-CM), and Sugen normoxia (SuNx + MSC-CM). The two latter groups were treated with conditioned media (CM) from HUCMSC. Animals underwent cardiac catheterization, echocardiography, MRI, histology/IHC, and electron microscopy. Rat whole lungs were harvested for multi-omics analysis. We also performed compassionate use of the first-in-human HUCMSC-CM infusions (2 i.p.a., 3 central venous), followed by HUCMSC transplantation (30 mio. cells), in a 3-year-old child with systemic PAH.

Results: Three intravenous injections of HUCMSC-CM (1) decreased pulmonary vessel thickness (remodeling) and right ventricular (RV) systolic pressure; (2) improved RV function; (3) impaired macrophage infiltration in the lung in conjunction with marked regulation of lipid and proinflammatory mediators, cell cycle factors, transcription factors and metabolic enzymes; (4) reduced RV hypertrophy; and (5) prevented cardiac mitochondrial disarray/damage, RV failure, and death. This was associated with pulmonary downregulation of LTB4, 15-HETE, Spp1, Nfatc2, all modulating PASMC proliferation, fibrosis, and inflammation. scRNA-seq and proteomics suggest increased activity of regeneration, autophagy, and anti-inflammation pathways, and mitochondrial function. We found boosted HUCMSC expression and secretion of prostaglandin E2, known to be regenerative. Finally, we pursued the first-in-human HUCMSC-CM infusions, followed by HUCMSC transplantation in severe PAH that led to hemodynamic and clinical improvement. Blood plasma markers of vascular fibrosis (NEDD9), injury (ICAM-1), and inflammation (IFN-gamma) decreased with HUCMSC-CM treatment. The girl is now 6.5 years old, has no exercise limitations, and only 66% systemic pressure in the pulmonary artery (mPAP/mSAP = 0.66; PVR/SVR: 0.62).

Conclusion: HUC and HUCMSC are readily available, and thus can be a game changer in future anti-remodeling/regenerative therapies, not only for PAH and RV failure, but also other progressive, debilitating heart-lung diseases (ARDS, IPF, BPD, left heart failure).

Publikationsverlauf

Artikel online veröffentlicht:
28. Januar 2023