Mesenchymal stem cells (MSCs) have the potential to promote liver regeneration, but the process is unclear. This study aims to explore the therapeutic effects and dynamic processes of MSCs in liver regeneration through intravoxel incoherent motion (IVIM) imaging.

70 adult Sprague-Dawley rats were randomly divided into either the control or MSC group (n = 35/group). All rats received a partial hepatectomy (PH) with the left lateral and middle lobes removed. Each group was divided into seven subgroups: pre-PH and 1, 2, 3, 5, 7, and 14 days post-PH (n = 5 rats/subgroup). Magnetic resonance imaging (MRI) was performed before obtaining pathological specimens at each time point on postoperative days 1, 2, 3, 5, 7, and 14. The MRI parameters for the pure diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction (PF) were calculated. Correlation analysis was conducted for the biochemical markers (alanine transaminase [ALT], aspartate transaminase [AST], and total bilirubin [TBIL]), histopathological findings (hepatocyte size and Ki-67 proliferation index), liver volume (LV) and liver regeneration rate (LLR).

Liver D, D* , and PF differed significantly between the control and MSC groups at all time points (all P < 0.05). After PH, the D increased, then decreased, and the D* and PF decreased, then increased in both groups. The hepatocyte Ki-67 proliferation index of the MSC group was lower on day 2 post-PH, but higher on days 3 and 5 post-PH than that of the control group. Starting from day 3 post-PH, both the LV and LLR in the MSC group were greater than those in the control group (all P < 0.05). Hepatocytes were larger in the MSC group than in the control group on days 2 and 7 post-PH. In the MSC group, the D, D* , and PF were correlated with the AST levels, Ki-67 index and hepatocyte size (|r|=0.35-0.71; P < 0.05). In the control group, the D and D* were correlated with ALT levels, AST levels, Ki-67 index, LLR, LV, and hepatocyte size (|r|=0.34-0.95; P < 0.05).

Bone marrow MSC therapy can promote hepatocyte hypertrophy and prolong liver proliferation post-PH. IVIM parameters allow non-invasively evaluating the efficacy of MSCs in promoting LR.

Despite climate-change challenges, for most aquaculture species, physiological responses to different salinities during ambient extreme cold events remain unknown. Here, European seabass acclimatized at 3, 6, 12, and 30 PSU were subjected to 20 days of an ambient extreme winter cold event (8 °C), and monitored for growth and physiological performance. Growth performance decreased significantly (p < 0.05) in fish exposed at 3 and 30 PSU compared to 6 and 12 PSU. During cold stress exposure, serum Na+, Cl-, and K+ concentrations were significantly (p < 0.05) increased in fish exposed at 30 PSU. Serum cortisol, glucose, and blood urea nitrogen (BUN) were increased significantly (p < 0.05) in fish exposed at 3 and 30 PSU. In contrast, opposite trends were observed for serum protein, lactate, and triglycerides content during cold exposure. Transaminase activities [glutamic-pyruvate transaminase (GPT), glutamic oxaloacetic transaminase (GOT), lactic acid dehydrogenase (LDH), gamma-glutamyl-transaminase (γGGT)] were significantly higher in fish exposed at 3 and 30 PSU on days 10 and 20. The abundance of heat shock protein 70 (HSP70), tumor necrosis factor-α (TNF-α), cystic fibrosis transmembrane conductance (CFTR) were significantly (p < 0.05) increased in fish exposed at 3 and 30 PSU during cold shock exposure. In contrast, insulin-like growth factor 1 (Igf1) expression was significantly lower in fish exposed at 3 and 30 PSU. Whereas, on day 20, Na+/K+ ATPase α1 and Na+/K+/Cl- cotransporter-1 (NKCC1) were significantly upregulated in fish exposed at 30 PSU, followed by 12, 6, and 3 PSU. Results demonstrated that ambient extreme winter cold events induce metabolic and physiological stress responses and provide a conceivable mechanism by which growth and physiological fitness are limited at cold thermal events. However, during ambient extreme cold (8 °C) exposure, European seabass exhibited better physiological fitness at 12 and 6 PSU water, providing possible insight into future aquaculture management options.

Chronic liver disease and cirrhosis is a widespread and untreatable condition that leads to lifelong impairment and eventual death. The scarcity of liver transplantation options requires the development of new strategies to attenuate disease progression and reestablish liver function by promoting regeneration. Biomaterials are becoming an increasingly promising option to both culture and deliver cells to support in vivo viability and long-term function. There is a wide variety of both natural and synthetic biomaterials that are becoming established as delivery vehicles with their own unique advantages and disadvantages for liver regeneration. We review the latest developments in cell transplantation strategies to promote liver regeneration, with a focus on the use of both natural and synthetic biomaterials for cell culture and delivery. We conclude that future work will need to refine the use of these biomaterials and combine them with novel strategies that recapitulate liver organization and function in order to translate this strategy to clinical use.

Orthotopic liver transplantation (OLT) is the only treatment for end-stage liver failure; however, graft shortage impedes its applicability. Therefore, studies investigating alternative therapies are plenty. Nevertheless, no study has comprehensively analyzed these therapies from different perspectives.

To summarize the current status of alternative transplantation therapies for OLT and to support future research.

A systematic literature search was performed using PubMed, Cochrane Library and EMBASE for articles published between January 2010 and 2018, using the following MeSH terms: [(liver transplantation) AND cell] OR [(liver transplantation) AND differentiation] OR [(liver transplantation) AND organoid] OR [(liver transplantation) AND xenotransplantation]. Various types of studies describing therapies to replace OLT were retrieved for full-text evaluation. Among them, we selected articles including in vivo transplantation.

A total of 89 studies were selected. There are three principle forms of treatment for liver failure: Xeno-organ transplantation, scaffold-based transplantation, and cell transplantation. Xeno-organ transplantation was covered in 14 articles, scaffold-based transplantation was discussed in 22 articles, and cell transplantation was discussed in 53 articles. Various types of alternative therapies were discussed: Organ liver, 25 articles; adult hepatocytes, 31 articles; fetal hepatocytes, three articles; mesenchymal stem cells (MSCs), 25 articles; embryonic stem cells, one article; and induced pluripotent stem cells, three articles and other sources. Clinical applications were discussed in 12 studies: Cell transplantation using hepatocytes in four studies, five studies using umbilical cord-derived MSCs, three studies using bone marrow-derived MSCs, and two studies using hematopoietic stem cells.

The clinical applications are present only for cell transplantation. Scaffold-based transplantation is a comprehensive treatment combining organ and cell transplantations, which warrants future research to find relevant clinical applications.

Biocompatible nanocomposite films based on chitosan (CS) and polyethylene glycol (PEG) polymers containing cephalexin (CFX) antibiotic drug and zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (NPs) were designed and fabricated to develop wound dressing materials capable of controlled drug release. Swelling experiment was performed in three acidic, neutral, and alkaline solutions. The tensile strength test reflected that upon increasing the NPs loading within the films, the tensile strength was enhanced but the elongation at break was diminished. The release of the CFX was intensively increased within approximately 3, 8, and 10 h (burst release) in acidic, neutral, and alkaline media, respectively while after that the CFX was smoothly released over time (sustained release). The antibacterial activities of all films were examined against Gram-positive (S. aureus, B. cereus) and Gram-negative (E. coli, P. aeruginosa, and Acinetobacter) bacteria frequently found in the infected wounds. Moreover, the MTT assay revealed that all films had high cell viabilities towards the L929 fibroblast cells confirming these nanocomposites could be used as favorable wound dressing materials. Finally, the film containing 4% ZIF-8 NPs (film 5) was chosen as the best sample due to it revealed appropriate mechanical properties, swelling, drug release and cell viability among all samples examined.

For the clinical application of stem cell therapy, functional enhancement is needed to increase the survival rate and the engraftment rate. The purpose of this study was to investigate functional enhancement of the paracrine effect using stem cells and hepatocyte-like cells and to minimize stem cell homing by using a scaffold system in a liver disease model.

A microporator was used to overexpress Foxa2 in adipose tissue-derived stem cells (ADSCs), which were cultured in a poly(lactic-co-glycolic acid) (PLGA) scaffold. Later, the ADSCs were cultured in hepatic differentiation medium for 2 weeks by a 3-step method. For in vivo experiments, Foxa2-overexpressing ADSCs were loaded in the scaffold, cultured in hepatic differentiation medium and later were implanted in the dorsa of nude mice subjected to acute liver injury (thioacetamide intraperitoneal injection).

Foxa2-overexpressing ADSCs showed greater increases in hepatocyte-specific gene markers (alpha fetoprotein [AFP], cytokeratin 18 [CK18], and albumin), cytoplasmic glycogen storage, and cytochrome P450 expression than cells that underwent the conventional differentiation method. In vivo experiments using the nude mouse model showed that 2 weeks after scaffold implantation, the mRNA expression of AFP, CK18, dipeptidyl peptidase 4 (CD26), and connexin 32 (CX32) was higher in the Foxa2-overexpressing ADSCs group than in the ADSCs group. The Foxa2-overexpressing ADSCs scaffold treatment group showed attenuated liver injury without stem cell homing in the thioacetamide-induced acute liver injury model.

Foxa2-overexpressing ADSCs applied in a scaffold system enhanced hepatocyte-like differentiation and attenuated acute liver damage in an acute liver injury model without homing effects.

Angiogenesis has always been a concern in the field of tissue engineering. Poor vascularization of engineered constructs is a problem for the clinical success of these structures. Among the various methods employed to induce angiogenesis, stem cells provide a promising tool for the future. The present review aims to present the application of stem cells in the induction of angiogenesis. Additionally, it summarizes recent advancements in stem cell-mediated angiogenesis of different tissue engineering constructs.

We used surface-modified titanium (Ti) substrates with a multilayered structure composed of chitosan-catechol (Chi-C), gelatin (Gel) and hydroxyapatite (HA) nanofibers, which were previously shown to improve osteogenesis, as a platform to investigate the interaction of osteogenesis and angiogenesis during bone healing. Combined techniques of Transwell co-culture, wound healing assay, enzyme linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical staining were used to evaluate adhesion, morphology and migration of adipose-derived mesenchymal stem cells (Ad-MSCs) and human umbilical vein endothelial cells (HUVECs) grown on different Ti substrates. We investigated the effect of substrates on the osteogenic differentiation of Ad-MSCs and reciprocal paracrine effects of Ad-MSCs on HUVECs or vice versa. The multilayered Ti substrates directly regulated the cellular functions of Ad-MSCs and angiogenic HUVECs and mediated communication between them by enhancing paracrine effects via cell-matrix interactions in vitro. The in vivo results showed that the change of microenvironment induced by surface-modified Ti implants promoted the adhesion, recruitment and proliferation of MSCs and facilitated coupled osteogenesis and angiogenesis in bone healing. The study proved that multilayer-film-coated Ti substrates positively mediated cellular biological function in vitro and improved bone healing in vivo.

Recent studies have revealed that osteogenesis and angiogenesis are coupled, and that communication between osteoblasts and endothelial cells is essential for bone healing and remodeling processes; however, these conclusions only result from in vitro studies or in vivo studies using transgenic murine models. Relatively little is known about the communication between osteoblasts and endothelial cells in peri-implants during bone healing processes. Our results revealed the cellular/molecular mechanism of how multilayered Ti substrates mediate reciprocal paracrine effects between adipose-derived mesenchymal stem cells and human umbilical vein endothelial cells; moreover, the interactions between the cell-matrix and peri-implant was proven in vivo with enhanced bone healing. This study contributes to our understanding of the fundamental mechanisms of angiogenesis and osteogenesis that affect peri-implantation, and thus, provides new insights into the design of future high-quality orthopedic implants.

Obesity is largely responsible for the growing incidence and prevalence of diabetes, cardiovascular and renal diseases. Current strategies to prevent and treat obesity and its consequences have been insufficient to reverse the ongoing trends. Lifestyle modification or pharmacological therapies often produce modest weight loss which is not sustained and recurrence of obesity is frequently observed, leading to progression of target organ damage in many obese subjects. Therefore, research efforts have focused not only on the factors that regulate energy balance, but also on understanding mechanisms of target organ injury in obesity. Summary and Key Message: Microvascular (MV) disease plays a pivotal role in progressive kidney injury from different etiologies such as hypertension, diabetes, and atherosclerosis, which are all important consequences of chronic obesity. The MV networks are anatomical units that are closely adapted to specific functions of nutrition and removal of waste in every organ. Damage of the small vessels in several tissues and organs has been reported in obesity and may increase cardio-renal risk. However, the mechanisms by which obesity and its attendant cardiovascular and metabolic consequences interact to cause renal MV injury and chronic kidney disease are still unclear, although substantial progress has been made in recent years. This review addresses potential mechanisms and consequences of obesity-induced renal MV injury as well as current treatments that may provide protection of the renal microcirculation and slow progressive kidney injury in obesity.