Liver sinusoidal endothelial and biliary cell repopulation following irradiation and partial hepatectomy

AIM: To investigate whether irradiation (IR) and partial hepatectomy (PH) may prepare the host liver for nonparenchymal cell (NPC) transplantation.METHODS: Livers of dipeptidyl peptidase(DPP)-deficient rats were pre-conditioned with external beam IR (25 Gy) delivered to two-thirds of the right liver lobules followed by a one-third PH of the untreated lob-ule. DPP-positive liver cells (NPC preparations enriched for liver sinusoidal endothelial cells (LSECs) and hepatocytes) were transplanted via the spleen into the recipient livers. The extent and quality of donor cell engraftment and growth was studied over a long-term interval of 16 wk after transplantation.RESULTS: Host liver staining demonstrated 3 different repopulation types. Well def ined clusters of donor-derived hepatocytes with canalicular expression of DPP were detectable either adjacent to or in between large areas of donor cells (covering up to 90% of the section plane) co-expressing the endothelial marker platelet endothelial cell adhesion molecule. The third type consisted of formations of DPP-positive duct-like structures which co-localized with biliary epithelial CD49f.CONCLUSION: Liver IR and PH as a preconditioning stimulus enables multiple cell liver repopulation by donor hepatocytes, LSECs, and bile duct cells.

Don’t know what you got till it’s gone:microglial depletion and neurodegeneration

In the central nervous system,immunologic surveillance and response are carried out,in large part,by microglia.These resident macrophages derive from myeloid precursors in the embryonic yolk sac,migrating to the brain and eventually populating local tissue prior to blood-brain barrier formation.Preserved for the duration of lifespan,microglia serve the host as more than just a central arm of innate immunity,also contributing significantly to the development and maintenance of neurons and neural networks,as well as neuroregeneration.The critical nature of these varied functions makes the characterization of key roles played by microglia in neurodegenerative disorders,especially Alzheimer’s disease,of paramount importance.While genetic models and rudimentary pharmacologic approaches for microglial manipulation have greatly improved our understanding of central nervous system health and disease,significant advances in the selective and near complete in vitro and in vivo depletion of microglia for neuroscience application continue to push the boundaries of research.Here we discuss the research efficacy and utility of various microglial depletion strategies,including the highly effective CSF1R inhibitor models,noteworthy insights into the relationship between microglia and neurodegeneration,and the potential for therapeutic repurposing of microglial depletion and repopulation.

Bioengineered humanized livers as better three-dimensional drug testing model system

AIM To develop appropriate humanized three-dimensional ex-vivo model system for drug testing. METHODS Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses.RESULTS The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available ex-vivo and in vivo models for identifying cellular and molecular dynamics of pharmacological drugs.CONCLUSION The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems.

Cell competition in liver carcinogenesis

Cell competition is now a well-established quality control strategy to optimize cell and tissue fitness in multicellular organisms.While pursuing this goal,it is also effective in selecting against altered/defective cells with putative(pre)-neoplastic potential,thereby edging the risk of cancer development.The flip side of the coin is that the molecular machinery driving cell competition can also be co-opted by neoplastic cell populations to expand unchecked,outside the boundaries of tissue homeostatic control.This review will focus on information that begins to emerge regarding the role of cell competition in liver physiology and pathology.Liver repopulation by normal transplanted hepatocytes is an interesting field of investigation in this regard.The biological coordinates of this process share many features suggesting that cell competition is a driving force for the clearance of endogenous damaged hepatocytes by normal donor-derived cells,as previously proposed.Intriguing analogies between liver repopulation and carcinogenesis will be briefly discussed and the potential dual role of cell competition,as a barrier or a spur to neoplastic development,will be considered.Cell competition is in essence a cooperative strategy organized at tissue level.One facet of such cooperative attitude is expressed in the elimination of altered cells which may represent a threat to the organismal community.On the other hand,the society of cells can be disrupted by the emergence of selfish clones,exploiting the molecular bar codes of cell competition,thereby paving their way to uncontrolled growth.

The 4Rs in radiation therapy

It has been realized that the 4Rs(repair,repopulation,redistribution,and reoxygenation)would affect the result of cell irradiation,and thus radiation treatment.The 4Rs each occurs at different dose rates,usually very low dose rates.Depending on the dose rate used for treatment,the corresponding R should be included in the linear-quadratic equation(LQ)and biological effective dose(BED)calculation.For low dose rate brachytherapy(LDR)especially permanent implant,all the 4Rs should be included in LQ for BED calculation.The 4Rs,especially repair and repopulation,play a critical role in dose fractionation.Various dose fractionation schemes such as hyperfractionation and hypofractionation are determined in consideration of the 4Rs.Stereotactic radiation therapy uses hypofractionation with high fractional doses and combine with high accuracy target localization techniques to achieve high local control rates compared to conventional dose fractionation schemes.The 4Rs have been taken into account for LDR and permanent implant.Recently,LQ for permanent implant brachytherapy has been modified to include all the 4Rs for gynecological malignancy 131 Cs permanent implants.Including the 4Rs in radiation therapy has significantly improved the effectiveness and efficiency of radiation therapy for cancer treatment.

Return to the hematopoietic stem cell origin

Studying embryonic hematopoiesis is complicated by diversity of its locations in the constantly changing anatomy and by the mobility of blood cell precursors.Embryonic hematopoietic progenitors are identified in traditional in vivo and in vitro cell potential assays.Profound epigenetic plasticity of mammalian embryonic cells combined with significant inductive capacity of the potential assays suggest that our understanding of hematopoietic ontogenesis is substantially distorted.Non-invasive in vivo cell tracing methodology offers a better insight into complex processes of blood cell specification.In contrast to the widely accepted view based on the cell potential assays,the genetic tracing approach identified the yolk sac as the source of adult hematopoietic stem cell lineage.Realistic knowledge of the blood origin is critical for safe and efficient recapitulation of hematopoietic development in culture.