Therapeutic Effect of Human Umbilical Cord Mesenchymal Stem Cells at Various Passages on Acute Liver Failure in Rats

Abstract

Recent studies have described beneficial effects of an infusion of mesenchymal stem cells (MSCs) derived from Wharton's jelly tissue, for the treatment of acute liver failure (ALF). However, data on the therapeutic potential of culture-expanded MSCs are lacking. We examined the therapeutic potential of passage five (P5) and ten (P10) human umbilical cord- (hUC-) MSCs via their transplantation into Sprague-Dawley (SD) rats with D-galactosamine (D-GalN) and LPS-induced acute liver failure (ALF). SD rats were randomly divided into three groups: control group, P5 hUC-MSCs group, and P10 hUC-MSCs group. After transplantation, P5 hUC-MSCs provided a significant survival benefit. The analysis of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) levels showed that transplantation with P5 hUC-MSCs was more effective than treatment with P10 hUC-MSCs. P5 hUC-MSCs also successfully downregulated the hepatic activity index (HAI) scores. Compared to P10 hUC-MSCs in vivo, P5 hUC-MSCs significantly enhanced the regeneration and inhibited the apoptosis of hepatocytes. CM-Dil-labeled hUC-MSCs were found to engraft within the recipient liver, whereas the homing of cells to the recipient liver in the P10 hUC-MSCs group was less effective compared to the P5 hUC-MSCs group. Previous studies have shown that the concentration of hepatocyte growth factor (HGF) in the injured liver was significantly increased. HGF is commonly known as the ligand of c-Met. The level of c-Met in hUC-MSCs as detected by Western blotting indicated that at a higher passage number, there is a decrease in c-Met. These data suggest that direct transplantation of P5 hUC-MSCs can more efficiently home to an injured liver. Subsequently, the P5 hUC-MSCs can rescue ALF and repopulate the livers of rats through the stimulation of endogenous liver regeneration and inhibition of hepatocellular apoptosis for compensated liver function, which is dependent on the higher level of c-Met than P10 hUC-MSCs.

Systematic comparison of hUC-MSCs at various passages reveals the variations of signatures and therapeutic effect on acute graft-versus-host disease

“…To date, although BM-MSCs act as the most widely used cells in clinical trials, yet hUC-MSCs possess superiority in large-scale expansion and standardization [31,36]. Of the listed factors, a number of studies indicated that long-term in vitro culture and continuous passages were the prohibiting factor for phenotype and function of MSCs, yet the evidence was still lacking [21,22,31]. Currently, even though we and other investigators have compared the biological signatures of hUC-MSCs with hBM-MSCs or hAD-MSCs in some respects at the cellular level, few of the studies are further focusing on the distinctions at the molecular level [21,37].…”

“…Recently, we and other investigators found the therapeutic effect of MSCs was closely related to cell viability and homing capacity, which was fundamental for clinical application and regenerative medicine [5,22]. Among the influencing factors, long-term in vitro passages would lead to the reduction of the abovementioned characteristics, together with the changes of biological properties and functions, such as the cytokine secretion, hematopoietic supporting and immunomodulating capacities, and even molecular biological alterations [1,2,9].…”

“…Of these studies, we and other investigators have indicated the efficacy of human umbilical cord mesenchymal stem cells (hUC-MSCs), which are promising sources without limitation in supply [15,20,21]. Moreover, the long-term effectiveness and quality of MSCs on the prognosis of the patients or animals mostly depend on cell vitality and homing ability of the infused cells [22]. Recently, Zhang et al showed that hUC-MSCs at various passages would result in different therapeutic effects on acute liver failure in rat, which indicated long term in vitro passages could attenuate the biological properties and act as a lingering problem pertaining to MSC-based clinical application [22].…”

“…Moreover, the long-term effectiveness and quality of MSCs on the prognosis of the patients or animals mostly depend on cell vitality and homing ability of the infused cells [22]. Recently, Zhang et al showed that hUC-MSCs at various passages would result in different therapeutic effects on acute liver failure in rat, which indicated long term in vitro passages could attenuate the biological properties and act as a lingering problem pertaining to MSC-based clinical application [22]. However, the systematic evaluation of in vitro passages on biological characteristics and functions of hUC-MSCs is still lacking, which is urgent for standardizing and guiding therapeutic purposes of MSCs [4,9].…”

Multifaceted characterization of the signatures and efficacy of mesenchymal stem/stromal cells in acquired aplastic anemia

“…Mesenchymal stem/stromal cells (MSCs) are heterogeneous populations capable of multipotential differentiation together with hematopoietic supporting and immunosuppressive properties [9][10][11]. MSCs have been wildly used in preclinical and clinical studies for disease remodeling including acute-on-chronic liver failure, diabetes, Crohn's disease, and acquired AA [9,[12][13][14][15][16]. Generally, as the key component in the microenvironment, MSCs serve as a potential supplementary alternative for refractory AA treatment and have exhibited unexceptionably therapeutic effect mainly through transdifferentiation, immunomodulatory activity, autocrine, and paracrine together with providing an ideal niche [17,18].…”