Abstract
Mesenchymal stem cells from Wharton's jelly of the human umbilical cord (hWJSCs), and the conditioned medium (hWJSC-CM) prepared from them, were shown to be tumoricidal on many cancers. However, these tumoricidal effects were observed in hWJSCs grown under normoxic conditions of 21% oxygen in the laboratory. Since oxygen concentrations in the stem cell niche or physiological microenvironment are hypoxic and help to maintain stemness properties, the objective of this work was to evaluate whether there were differences in the tumoricidal properties of hWJSC-CM grown in 21% O2 (normoxic) or 5% O2 (hypoxic) environments. The results showed that hWJSCs grown under normoxic or hypoxic conditions showed no distinct morphological differences in culture and remained positive in trilineage differentiation into adipocytes, osteocytes, and chondrocytes. Hypoxic hWJSCs expressed the mesenchymal stem cell surface markers CD105, CD90, CD73, CD146, and CD108 similar to normoxic hWJSCs but were negative for the hematopoietic markers CD14, CD19, CD34, CD45, CD117, and HLA-DR. Hypoxic hWJSC-CM produced a significantly greater reduction in cell viability and a significantly greater increase in apoptosis, oxidative stress, and lipid peroxidation in human lymphoma cells compared to normoxic hWJSC-CM. Hypoxic hWJSC-CM also produced significantly greater expression of immunogenic cell death (ICD) hallmarks such as surface-bound calreticulin, HSP70, HSP90, and high mobility group binding 1 proteins and significantly decreased expression of the defense molecules CD47 and PD-L1. This study showed that the tumoricidal effect of hypoxic hWJSC-CM was superior to normoxic hWJSC-CM and should be the preferred choice of preparing hWJSC-CM for the induction of ICD on lymphoma cells.
Highlights
Primitive populations of mesenchymal stems cells have been derived from the gelatinous connective tissue matrix (Wharton’s jelly) of the human umbilical cord [1, 2]
Unengineered Human Wharton’s jelly stem cell (hWJSC) homed into and reduced the tumor burden in human breast carcinomas xenografted in the rat when injected intravenously [6]. hWJSCs stopped the proliferation of breast cancer cells by secreting dickkopf and suppressing the Wnt pathway in xenograft mice [11]
The results showed that there were significant decreases in CD47 expression in lymphoma cells exposed to normoxic or hypoxic hWJSC-CM compared to controls
Summary
Primitive populations of mesenchymal stems cells have been derived from the gelatinous connective tissue matrix (Wharton’s jelly) of the human umbilical cord (hWJSCs) [1, 2] These hWJSCs originate from the aorta-gonadmesonephros and through their movement come to reside in Wharton’s jelly during early human development [3]. They can be harvested in large numbers, can proliferate rapidly, and have been widely used in the clinic to treat a variety of diseases as they do not form tumors and have high tolerance in transplantation settings [4, 5]. Some research groups have shown that hWJSC-CM or microvesicles derived from hWJSCs inhibited phosphoinositide 3-kinase, Akt, and Wnt/B-catenin signalling in bile duct or urinary tract cancer cells, respectively, to stop their growth [15, 16]
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