Human umbilical cord mesenchymal stem cell-derived treatment of severe pulmonary arterial hypertension

Abstract

Here we report application of human umbilical cord mesenchymal stem cell (HUCMSC)-derived therapy for pulmonary arterial hypertension (PAH). A 3-year-old female presented with heritable PAH associated with hereditary hemorrhagic telangiectasia and was treated for 6 months with serial intravascular infusions of conditioned media (CM) from allogenic HUCMSCs. The treatment markedly improved clinical and hemodynamic parameters and decreased blood plasma markers of vascular fibrosis, injury and inflammation. A comparative analysis of single-cell RNA sequencing data collected from three HUCMSCs and two human umbilical vein endothelial cell (HUVEC) controls identified eight common cell clusters, all of which indicated regenerative potential specific for HUCMSCs. The properties of HUCMSCs were validated by untargeted label-free quantitation of the cell and CM proteome, suggesting increased activity of regeneration, autophagy and anti-inflammation pathways and mitochondrial function. Prostaglandin analysis demonstrated increased HUCMSC secretion of prostaglandin E2, known for its regenerative capacity. Additional prospective clinical studies are warranted to confirm and further explore the benefits of HUCMSC-derived therapy for PAH.

Pulmonary Arterial Hypertension: Emerging Principles of Precision Medicine across Basic Science to Clinical Practice

“…Mesenchymal stem cells and secreted of circulating microvesicles have displayed therapeutic properties in experimental models. Recent administration of conditioned media from such stem cells resulted in clinical and hemodynamic improvement of severe PAH in a single pediatric patient [ 196 ]. Yet, given the extreme pleiotropy of these stem cells and their microvesicle content, identification of the exact causative components of this biology has been challenging.…”

Mesenchymal stem cell secretome-loaded fibrin glue improves the healing of intestinal anastomosis

“…Multiple fundamental studies support the application of MSC-derived secretome in the reconstruction of injured organs or tissues (Rhatomy et al, 2020;Lin et al, 2021). Furthermore, clinical trials have shown that MSCs-derived secretome is promising in the treatment of hereditary pulmonary arterial hypertension (Hansmann et al, 2022), protection against skin aging (Sushmitha et al, 2018;Liang et al, 2022), and hair regeneration (Shin et al, 2018). Although the MSCs-derived secretome holds strong potential to promote regeneration and repair, unfortunately, there are currently no reports on its role in anastomotic healing.…”

Can Mesenchymal Stem Cell–Derived Therapeutics Protect the Developing Brain During Cardiac Surgery?

“…Whereas certain priming measures in MSCs might increase their transdifferentiation, engraftment, and anti-inflammatory/proregenerative potency, 2 the major beneficial effects of MSCs are widely accepted to be of paracrine nature (secretion). The MSC secretome, harvested as MSC-CM (cell culture supernatant), contains several key factors boosting regeneration, autophagy, immunomodulation/anti-inflammation (monocyte/macrophage reprogramming), and mitochondrial function; those beneficial CM components include, for example, the proteins APOE, LRP1, P38, as well as PGE2 (in human umbilical cord [HUC] MSC-CM), 3 and EVs, that is, microvesicles (ID <1,000 nm) 4 and exosomes (ID <150 nm), containing multiple RNAs, proteins, and lipid rafts. 4 These CM components, applied either as an “unfiltered CM cocktail” 3 or highly concentrated EVs, are probably equally effective as, if not superior to, MSC infusions.…”

“…A comparative single-cell RNA-sequencing transcriptomic analysis of therapeutic HUC MSCs vs nontherapeutic human umbilical vein endothelial cells, and the accordingly successful first-in-human HUC MSC-CM treatment of a child with severe cardiovascular disease, have recently been published. 3 Hence, there is a good rationale to test delivery of HUC MSCs and/or their secreted products (CM or EVs) in the juvenile piglet CPB and rodent/porcine stroke models. Repetitive dosing of MSC-EVs within a few days has been shown to be superior to large single dosing.…”

“…Moreover, MSC or MSC-product administration may be even more neuroprotective when started 24-48 hours before CPB-cardiac surgery. Repetitive dosing of HUC MSC-CM has recently been conducted in a clinical case of severe pulmonary arterial hypertension, 3 thereby driving regeneration, mitochondrial function, anti-inflammation/immunomodulation, and autophagy, counteracting inflammation, pulmonary artery smooth muscle cell proliferation, and fibrosis. Hence, for future animal or clinical phase 1/2 studies, intravenous or intra-arterial MSC-derived therapeutics should probably be best administered in a repetitive fashion, starting well before the expected neurologic insult.…”