Myocardial regeneration strategy using Wharton’s jelly mesenchymal stem cells as an off-the-shelf ‘unlimited’ therapeutic agent: results from the Acute Myocardial Infarction First-in-Man Study

Abstract

IntroductionIn large-animal acute myocardial infarction (AMI) models, Wharton's jelly (umbilical cord matrix) mesenchymal stem cells (WJMSCs) effectively promote angiogenesis and drive functional myocardial regeneration. Human data are lacking.AimTo evaluate the feasibility and safety of a novel myocardial regeneration strategy using human WJMSCs as a unique, allogenic but immuno-privileged, off-the-shelf cellular therapeutic agent.Material and methodsThe inclusion criterion was first, large (LVEF ≤ 45%, CK-MB > 100 U/l) AMI with successful infarct-related artery primary percutaneous coronary intervention reperfusion (TIMI ≥ 2). Ten consecutive patients (age 32–65 years, peak hs-troponin T 17.3 ±9.1 ng/ml and peak CK-MB 533 ±89 U/l, sustained echo LVEF reduction to 37.6 ±2.6%, cMRI LVEF 40.3 ±2.7% and infarct size 20.1 ±2.8%) were enrolled.Results30 × 106 WJMSCs were administered (LAD/Cx/RCA in 6/3/1) per protocol at ≈ 5–7 days using a cell delivery-dedicated, coronary-non-occlusive method. No clinical symptoms or ECG signs of myocardial ischemia occurred. There was no epicardial flow or myocardial perfusion impairment (TIMI-3 in all; cTFC 45 ±8 vs. 44 ±9, p = 0.51), and no patient showed hs-troponin T elevation (0.92 ±0.29 ≤ 24 h before vs. 0.89 ±0.28 ≤ 24 h after; decrease, p = 0.04). One subject experienced, 2 days after cell transfer, a transient temperature rise (38.9°C); this was reactive to paracetamol with no sequel. No other adverse events and no significant arrhythmias (ECG Holter) occurred. Up to 12 months there was one new, non-index territory lethal AMI but no adverse events that might be attributable to WJMSC treatment.ConclusionsThis study demonstrated the feasibility and procedural safety of WJMSC use as off-the-shelf cellular therapy in human AMI and suggested further clinical safety of WJMSC cardiac transfer, providing a basis for randomized placebo-controlled endpoint-powered evaluation.

Concise Review: Mesenchymal Stem Cells in Cardiovascular Regeneration: Emerging Research Directions and Clinical Applications

“…WJ is also a promising source of MSCs for clinical application in treating acute myocardial infarction. WJ‐MSCs have been shown to be safe and beneficial in two independent studies , and had also positive effects on infarct size and left ventricular contractility .…”

“…However, MSCs are also found in umbilical cord blood , dental pulp , synovial fluid , amniotic fluid , and urine . Umbilical cord Wharton's jelly (WJ)‐derived MSCs have recently been gaining significant attention, owing to some of their unique properties and their feasibility of use as an “unlimited” off‐the‐shelf source of regenerative cells .…”

Stiffness‐controlled three‐dimensional collagen scaffolds for differentiation of human Wharton's jelly mesenchymal stem cells into cardiac progenitor cells

“…Previous studies have shown that transplanted bone marrow‐derived MSCs and Wharton's jelly MSCs can improve cardiac function in a rat model . The feasibility and procedural safety of Wharton's jelly MSCs in human MI have been demonstrated . Although transplantation of MSCs has advantages for cell therapy, low cell engraftment limits its implication .…”

Looking Beyond Reperfusion

“…To address these issues, a number of approaches to the modification of MSCs with the aim to improve their survival and proliferation, to reduce the immune reaction, enhance transdifferentiation, and optimize the profile of secreted paracrine factors have been tested [69]. It has been demonstrated that Wharton's jelly-derived mesenchymal stem cells (WJMSCs), a primitive stromal population, could integrate into ischemic cardiac tissues and significantly improve heart function [70,71]. The discovery of adult cardiac stem cells (CSCs) and their potential to restore functional cardiac tissue has fuelled unprecedented interest in recent years.…”