The assessment of multipotent cell transplantation in acute-on-chronic liver failure: a systematic review and meta-analysis.

Acute-on-chronic liver failure (ACLF) is a serious life-threatening disease with high prevalence. Liver transplantation is the only efficient clinical treatment for ACLF. Because of the rapid progression and lack of liver donors, it is urgent to find an effective and safe therapeutic approach to ACLF. Recent studies showed that multipotent cell transplantation could improve the patients' liver function and enhance their preoperative condition. Cells such as mesenchymal stem cells, bone marrow mononuclear cells and autologous peripheral blood stem cells, which addressed in this study have all been used in multipotent cell transplantation for liver diseases. However, its clinical efficiency is still debatable. This systematic review and meta-analysis explored the clinical efficiency of multipotent cell transplantation as a therapeutic approach for patients with ACLF. A detailed search of the Cochrane Library, MEDLINE, and Embase databases was conducted from inception to November 2017. The outcome measures were serum albumin, prothrombin time, alanine aminotransferase, total bilirubin, platelets, hemoglobin, white blood cells, and survival time. The quality of evidence was assessed using GRADEpro and Jaded scores. A literature search resulted in 537 citations. Of these, 9 articles met the inclusion criteria. It was found that multipotent cell transplantation was able to alleviate liver damage and improve liver function. Multipotent cell transplantation can also enhance the short-term and medium-term survival rates of ACLF. All 9 research articles included in this analysis reported no statistically significant adverse events, side effects, or complications. In conclusions, this study suggested that multipotent cell transplantation could be recommended as a potential therapeutic supplementary tool in clinical practice. However, clinical trials in large-volume centers still needed.

Synergism of human amnion-derived multipotent progenitor (AMP) cells and a collagen scaffold in promoting brain wound recovery: pre-clinical studies in an experimental model of penetrating ballistic-like brain injury.

One of the histopathological consequences of a penetrating ballistic brain injury is the formation of a permanent cavity. In a previous study using the penetrating ballistic-like brain injury (PBBI) model, engrafted human amnion-derived multipotent progenitor (AMP) cells failed to survive when injected directly in the injury tract, suggesting that the cell survival requires a supportive matrix. In this study, we seated AMP cells in a collagen-based scaffold, injected into the injury core, and investigated cell survival and neuroprotection following PBBI. AMP cells suspended in AMP cell conditioned medium (ACCS) or in a liquefied collagen matrix were injected immediately after a PBBI along the penetrating injury tract. Injured control rats received only liquefied collagen matrix. All animals were allowed to survive two weeks. Consistent with our previous results, AMP cells suspended in ACCS failed to survive; likewise, no collagen was identified at the injury site when injected alone. In contrast, both AMP cells and the collagen were preserved in the injury cavity when injected together. In addition, AMP cells/collagen treatment preserved some apparent brain tissue in the injury cavity, and there was measurable infiltration of endogenous neural progenitor cells and astrocytes into the preserved brain tissue. AMP cells were also found to have migrated into the subventricular zone and the corpus callosum. Moreover, the AMP cell/collagen treatment significantly attenuated the PBBI-induced axonal degeneration in the corpus callosum and ipsilateral thalamus and improved motor impairment on rotarod performance. Overall, collagen-based scaffold provided a supportive matrix for AMP cell survival, migration, and neuroprotection.

Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction.

The study examined the long-term outcome of cardiac stem cell transplantation in hearts with postinfarction left ventricular (LV) remodeling. Myocardial infarction (MI) was created by ligating the first and second diagonal branches of the left anterior descending coronary artery in miniature swine. Intramyocardial injections of 50 million LacZ-labeled bone marrow-derived multipotent progenitor cells (MPC) were performed in the periscar region (Cell, n = 7) immediately after MI, whereas, in control animals (Cont, n = 7), saline was injected. Functional outcome was assessed monthly for 4 mo with MRI and (31)P-magnetic resonance spectroscopy. Engraftment was studied on histology, and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (Cell, 43.4 +/- 5.1% vs. Cont, 32.2 +/- 5.5%; P < 0.05). This improvement was seen each month and persisted to 4 mo (Cell, 51.2 +/- 4.8% vs. Cont, 35.7 +/- 5.0%; P < 0.05). PCr-to-ATP ratio (PCr/ATP) improved with MPC transplantation, which was most pronounced at high cardiac work states (subendocardial PCr/ATP was 1.70 +/- 0.10 vs. 1.34 +/- 0.14, P < 0.05). There was no significant difference in scar size (scar/LV area * 100) at 10 days postinfarction. However, at 4 mo, there was a significant decrease in scar size in the Cell group (Cell, 4.6 +/- 1.0% vs. Cont, 8.6 +/- 2.4%; P < 0.05). No significant engraftment of MPC was observed. MPC transplantation was associated with a downregulation of mitochondrial oxidative enzymes and increased levels of myocyte enhancer factor 2a and zinc finger protein 91. In conclusion, MPC transplantation leads to long-term functional and bioenergetic improvement in a porcine model of postinfarction LV remodeling, despite no significant engraftment of stem cells in the heart. MPC transplantation reduces regional wall stresses and infarct size and mitigates the adverse effects of LV remodeling, as seen by a reduction in LV hypertrophy and LV dilatation, and is associated with differential expression of genes relating to metabolism and apoptosis.

Bioenergetic and functional consequences of bone marrow-derived multipotent progenitor cell transplantation in hearts with postinfarction left ventricular remodeling.

BACKGROUND: The present study examined whether transplantation of adherent bone marrow-derived stem cells, termed pMultistem, induces neovascularization and cardiomyocyte regeneration that stabilizes bioenergetic and contractile function in the infarct zone and border zone (BZ) after coronary artery occlusion. METHODS AND RESULTS: Permanent left anterior descending artery occlusion in swine caused left ventricular remodeling with a decrease of ejection fraction from 55+/-5.6% to 30+/-5.4% (magnetic resonance imaging). Four weeks after left anterior descending artery occlusion, BZ myocardium demonstrated profound bioenergetic abnormalities, with a marked decrease in subendocardial phosphocreatine/ATP (31P magnetic resonance spectroscopy; 1.06+/-0.30 in infarcted hearts [n=9] versus 1.90+/-0.15 in normal hearts [n=8; P<0.01]). This abnormality was significantly improved by transplantation of allogeneic pMultistem cells (subendocardial phosphocreatine/ATP to 1.34+/-0.29; n=7; P<0.05). The BZ protein expression of creatine kinase-mt and creatine kinase-m isoforms was significantly reduced in infarcted hearts but recovered significantly in response to cell transplantation. MRI demonstrated that the infarct zone systolic thickening fraction improved significantly from systolic "bulging" in untreated animals with myocardial infarction to active thickening (19.7+/-9.8%, P<0.01), whereas the left ventricular ejection fraction improved to 42.0+/-6.5% (P<0.05 versus myocardial infarction). Only 0.35+/-0.05% donor cells could be detected 4 weeks after left anterior descending artery ligation, independent of cell transplantation with or without immunosuppression with cyclosporine A (with cyclosporine A, n=6; no cyclosporine A, n=7). The fraction of grafted cells that acquired an endothelial or cardiomyocyte phenotype was 3% and approximately 2%, respectively. Patchy spared myocytes in the infarct zone were found only in pMultistem transplanted hearts. Vascular density was significantly higher in both BZ and infarct zone of cell-treated hearts than in untreated myocardial infarction hearts (P<0.05). CONCLUSIONS: Thus, allogeneic pMultistem improved BZ energetics, regional contractile performance, and global left ventricular ejection fraction. These improvements may have resulted from paracrine effects that include increased vascular density in the BZ and spared myocytes in the infarct zone.