Effect of Secreted Molecules of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells on Acute Hepatic Failure Model

Abstract

Adult tissue-derived mesenchymal stem cells (MSCs) show tremendous promise for a wide array of therapeutic applications predominantly through paracrine activity. Recent reports showed that human embryonic stem cell (ESC)-derived MSCs are an alternative for regenerative cellular therapy due to manufacturing large quantities of MSCs from a single donor. However, no study has been reported to uncover the secretome of human ESCMSCs as treatment of an acute liver failure (ALF) mouse model. We demonstrated that human ESC-MSCs showed similar morphology and cell surface markers compared with bone marrow-derived MSCs. ESC-MSCs exhibited a higher growth rate during early in vitro expansion, along with adipogenic and osteogenic differentiation potential. Treatment with ESC-MSC-conditioned medium (CM) led to statistically significant enhancement of primary hepatocyte viability and increased immunomodulatory interleukin-10 secretion from lipopolysaccharide-induced human blood mononuclear cells. Analysis of the MSCs secretome by a protein array screen showed an association between higher frequencies of secretory proteins such as vascular endothelial growth factor (VEGF) and regulation of cell proliferation, cell migration, the development process, immune system process, and apoptosis. In this thioacetamide-induced mouse model of acute liver injury, we observed that systemic infusion of VEGF led to significant survival. These data have provided the first experimental evidence of the therapeutic potential of human ESC-MSC-derived molecules. These molecules show trophic support to hepatocytes, which potentially creates new avenues for the treatment of ALF, as an inflammatory condition.

Human adipose‑derived mesenchymal stem cell‑conditioned media suppresses inflammatory bone loss in a lipopolysaccharide‑induced murine model

“…These inflammatory diseases include periodontitis, rheumatoid arthritis and inflammatory bowel disease ( 2 – 4 ). Patients suffering from inflammatory bone loss typically have an increased risk of morbidity and mortality, which may seriously impair their quality of life and thus cause a heavy economic burden ( 5 , 6 ). Therefore, intervention strategies through which inflammatory bone loss can be mitigated are highly valuable.…”

Efficient Isolation and Enrichment of Mesenchymal Stem Cells from Human Embryonic Stem Cells by Utilizing the Interaction between Integrin α5β1 and Fibronectin

“…The utilization of ECMs to develop efficient methods to isolate MSCs or mesodermal progenitor‐like cells from hESCs and hiPSCs remains largely unexplored. [ 2,5,11 ] Fibronectin, FN is a large ECM glycoprotein that triggers biochemical and mechanical signaling via integrin binding. Another hypothesis for the efficacy of this method is ECM remodeling in the earliest stages of embryonic development.…”

“…Representatively, selected small‐molecules, [ 6 ] spontaneously differentiating embryoid bodies (EBs), [ 2,7 ] cytokine/growth factor combinations, [ 8,9 ] coculturing systems, [ 10 ] and fluorescence‐activated cell sorting (FACS) after MSCs derivation/differentiation [ 2,5 ] have been reported. In addition, simplified techniques using physical cues, such as biomimetic fibrillar collagen, [ 5 ] gelatin, [ 2 ] and Matrigel, [ 2,11 ] have been utilized to derive MSCs from PSCs. However, unfortunately, the efficient and simplified methods are yet to be fully established to overcome the limitations of previous methods.…”

Co-encapsulation of HNF4α Overexpressing UMSCs and Human Primary Hepatocytes Ameliorates Mouse Acute Liver Failure

“…Mounting evidence showed that MSCs secretions exerted a bene cial effect by reducing the in ammatory response, promoting the survival and proliferation of injured cells, and ameliorating liver injury. (21,(44)(45)(46)(47) In the present study, microcapsules were used as carriers to encapsulate UMSCs and hepatocytes to persistently release the secretory factors contributing to the repair of impaired liver and the reduction of in ammatory response in ALF. And more, HNF4α-UMSCs signi cantly argument the therapeutic effects on ALF mice (Fig.1-5).…”