Stem Cell and Liver Regeneration (Frontiers in Hepatology)

Current Perspectives Regarding Stem Cell-Based Therapy for Liver Cirrhosis

However, the significance of LPC activation during recovery from acute liver injury remains subject of controversy. Lineage tracing models utilizing reporter mouse models might represent a feasible tool to quantify the contribution of LPC during regeneration Malato et al. At present, the only curative treatment for patients with fulminant hepatic failure is an ELT. However, this is significantly limited by the shortage of suitable donor organs. As such, hepatocyte cell transplantation has been evaluated as an alternative for those ineligible for liver transplantation, or as a bridge to liver transplant.

This is particularly attractive because cryopreserved cells are readily available. However, the number of cells that can be delivered via the portal vein is limited by the risks of portal hypertension Weber et al. LPC, on the other hand, are small in size, and are capable of differentiating into both hepatocytes and cholangiocytes Sandhu et al. Previously, the limiting factor in the study of LPC has been the inability to identify, isolate or purify these cells in a reliable fashion. We have similarly developed a LPC isolation protocol for mouse and human liver tissue, but using fluorescence-activated cell sorting FACS.

Our technique was based on the observation that progenitor cells express high levels of aldehyde dehydrogenase ALDH activity. A non-parenchymal cell population that might have an implication in liver regeneration are hepatic stellate cells. The contribution of stem cells in tissue repair remains controversial, but prevailing evidence suggest that bone marrow or adipose tissue derived MSCs might contribute to liver regeneration through differentiation Sato et al. Hepatic stellate cells could possibly fulfill a dual role as supportive cells producing a connective tissue scaffold facilitating LPC expansion and migration on the one hand and as progenitor cells on the other Yang et al.

The inter-relationship between liver and non-liver progenitor or stem cells i. Further studies will be necessary to understand and tap this potential source of new liver cells. Administration of granulocyte colony stimulating factor G-CSF during myocardial infarction for example, leads to the mobilization and differentiation of HSC to a committed lineage Theiss et al. Therefore, a potential attempt to enhance liver regeneration during ALF might be a mobilization of bone marrow progenitor cells by an administration of G-CSF. Cumulative data to date suggest that the LPC compartment is activated when there is confluent loss of hepatocyte mass, that lead to insufficient regenerative capacity of residual hepatocytes.

The cytokine storm that ensues during acute liver injury, in combination with growth factors, morphogens, hormones, and neurotransmitters, all act in concert to dictate the LPC response. This is unsurprising as hepatocyte cell death is intricately associated with liver repair i. Currently used scoring systems have not been able to reliably predict those who may survive from ALF.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Stem cells in liver regeneration, fibrosis and cancer: Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers. Cytokeratin based modification of the MELD score improves prediction of spontaneous survival after acute liver injury. Apoptosis versus necrosis rate as a predictor in acute liver failure following acetaminophen intoxication compared with acute-on-chronic liver failure.

Tri-iodothyronine as a stimulator of liver regeneration after partial and subtotal hepatectomy. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. The role of hedgehog signaling pathway in liver regeneration. Expression of suppressors of cytokine signaling during liver regeneration. Efficient generation of human hepatocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep.

Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Acute and acute severe fulminant autoimmune hepatitis. Acute liver failure is associated with elevated liver stiffness and hepatic stellate cell activation. Lessons from animal models of NASH. Successful isolation of liver progenitor cells by aldehyde dehydrogenase activity in naive mice. The quest for liver progenitor cells: Stem cells and liver regeneration.

Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Liver regeneration and repair: Locating the stem cell niche and tracing hepatocyte lineages in human liver. Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. Expression of stem cell factor and its receptor, c-kit, during liver regeneration from putative stem cells in adult rat.


Pubmed Abstract Pubmed Full Text. Apoptosis in liver diseases—detection and therapeutic applications. Marrow-derived mesenchymal stem cells restore biochemical markers of acute liver injury in experimental model. Prognostic implications of lactate, bilirubin, and etiology in German patients with acute liver failure. Etiologies and outcomes of acute liver failure in Germany. Significance of sonic hedgehog signaling after massive hepatectomy in a rat.

Liver Regeneration through Autologous Bone Marrow Cell Infusion Therapy - Yamaguchi University

Cloning Stem Cells 4, — Stem cell factor stimulates the chemotaxis, integrin upregulation, and survival of human basophils. Stem cell factor and c-kit are involved in hepatic recovery after acetaminophen-induced liver injury in mice. Fulminant and subfulminant hepatitis: Presse Med 38, — TWEAK induces liver progenitor cell proliferation. Hepatitis B-associated acute liver failure: Somatostatin stimulates the migration of hepatic oval cells in the injured rat liver. Signals from dying hepatocytes trigger growth of liver progenitors.

Remodelling of extracellular matrix is a requirement for the hepatic progenitor cell response. Defective liver regeneration after partial hepatectomy in mice lacking fibroblast growth factor inducible Liver regeneration in acute severe liver impairment: Hepatic stem cell niches. Triiodothyronine accelerates differentiation of rat liver progenitor cells into hepatocytes.

Thyroid hormone metabolism during liver regeneration in rats. Bone marrow-derived mesenchymal stem cells promote hepatic regeneration after partial hepatectomy in rats. Stemness in human thyroid cancers and derived cell lines: J Clin Endocrinol Metab Thyroid cancer stem cells. Nat Rev Endocrinol 7 Epithelial-mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells. Int J Oncol 43 1: Fetal cell carcinogenesis of the thyroid: Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors.

Physiol Rev 72 3: Cell population kinetics in dog and human adult thyroid. Clin Endocrinol Oxf 31 6: Compensatory thyroid hypertrophy after hemithyroidectomy in rats. Endocrinology 99 4: An experimental study of thyroid regeneration following subtotal thyroidectomy. Surg Gynecol Obstet 93 3: Thyroid gland formation from inocula of monodispersed cells: Hormonal effects on the quantitative transplantation of monodispersed rat thyroid cells. Restoration of thyroid function after total thyroidectomy and quantitative thyroid cell transplantation. Endocrinology 9: Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo.

J Exp Med 4: Nat Med 7 9: Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell 8 2: Asakura A, Rudnicki MA. Side population cells from diverse adult tissues are capable of in vitro hematopoietic differentiation. Exp Hematol 30 Kidney Int 65 5: Side population cells derived from adult human liver generate hepatocyte-like cells in vitro.

Dig Dis Sci 50 Cells of the hepatic side population contribute to liver regeneration and can be replenished with bone marrow stem cells. Haematologica 88 4: Sca-1 pos cells in the mouse mammary gland represent an enriched progenitor cell population. Dev Biol 1: Dystrophin expression in the mdx mouse restored by stem cell transplantation. A side order of stem cells: Stem Cells 24 1: Expression of endoderm stem cell markers: Thyroid 16 6: Stem cells derived from goiters in adults form spheres in response to intense growth stimulation and require thyrotropin for differentiation into thyrocytes.

J Clin Endocrinol Metab 92 9: J Endocrinol 3: Derivation and characterization of thyrocyte-like cells from embryonic stem cells in vitro. Methods Mol Biol Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science Colon cancer stem cells.

Voog J, Jones DL.


In addition, sophisticated methods of tracking engrafted MSCs are still lacking. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Hepatocytes from non-hepatic adult stem cells. Thyroid follicle formation and thyroglobulin expression in multipotent endodermal stem cells. Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Mechanistically, IRI consists of two phases, an early ischemic insult, characterized by metabolic perturbations, hypoxia and ATP depletion, and an inflammatory reperfusion injury mediated mostly by Kupffer cells that become activated upon response to hepatocellular damage signals 59 , Elucidating the metabolic regulation of liver regeneration.

Stem cells and the niche: Cell Stem Cell 6 2: The stem cell niche in regenerative medicine. Cell Stem Cell 10 4: Animal models for growth. Proc Nutr Soc 39 3: Experimental aspects of hepatic regeneration. N Eng J Med Hypothyroidism in the adult rat causes brain region-specific biochemical dysfunction. J Endocrinol 2: The influence of hypothyroidism on liver regeneration: Acta Cir Bras 22 Suppl 1: Decreased hypothalamic growth hormone-releasing hormone content and pituitary responsiveness in hypothyroidism.

J Clin Invest 77 5: Thyroid hormones alter Arrhenius kinetics of succinate-2,6-dichloroindophenol reductase, and the lipid composition and membrane fluidity of rat liver mitochondria. Eur J Biochem 2: J Endocrinol 1: Thyroid hormone regulation of heme oxidation in the liver. Endocrinology 5: Stem cell antigen 1-positive mesenchymal cells are the origin of follicular cells during thyroid regeneration.

PLoS One 8 Thyrocyte-specific expression of Cre recombinase in transgenic mice. Genesis 39 3: Murine models for the study of thyroid gland development. Endocr Dev Molecular targeting regulation of proliferation and differentiation of the bone marrow-derived mesenchymal stem cells or mesenchymal stromal cells.

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Curr Drug Targets 13 4: Stem cell homing in musculoskeletal injury. Biomaterials 32 2: Bone marrow mesenchymal cells: Arch Immunol Ther Exp Warsz 59 5: Bone marrow stem cells repopulate thyroid in X-ray regeneration in mice. Pathophysiology 19 1: Regenerative potentials of the murine thyroid in experimental autoimmune thyroiditis: Endocrinology 1: Oct4 expression in adult human stem cells: Carcinogenesis 26 2: Embryologic origin of the various epithelial cell types in the second kind of thyroid follicle in the C3H mouse. Anat Rec 1: Hox group 3 paralogs regulate the development and migration of the thymus, thyroid, and parathyroid glands.

Fine structure of a second kind of thyroid follicle in the C3H mouse. Endocrinology 84 3: Neve P, Wollman SH. Fine structure of ultimobranchial follicles in the thyroid gland of the rat. Anat Rec 2: Wollman SH, Neve P. Recent studies identified two different functional types of MSC. After chondrogenic differentiation the immunological properties of xenogeneic MSC changed. Yet, osteogenic, chondrogenic and adipogenic differentiation did not alter the immunosuppressive properties of MSC Chen et al. It may be concluded that MSC may play a pleiotropic role impacting a given disease by a specified mode of action, which is triggered by the diseased tissue environment.

This includes tissue regeneration through substitution of the tissue lesion by functional cells differentiated from the MSC but also modulation of an inflammatory tissue environment thus improving or stimulating self-regeneration of the affected tissue. These pleiotropic mode of action is highly appreciated to treat liver diseases of different etiology.

Acute or chronic liver injuries require the down-regulation of inflammatory processes in order to prevent progressing tissue damage whereas ample liver resection due to liver cancer might require substitution of functional loss. Hence, in the one case undifferentiated MSC might represent the cell source of choice while in the latter hepatocyte-differentiated MSC might be appreciated. It must be anticipated that nearly all tissues harbor MSC, which upon tissue injury proliferate and differentiate into the cells of the tissue of origin to replace and functionally regenerate the injured tissue regions.

Recently, MSC-like cells have even been isolated from adult human liver Najimi et al. So why not use MSC for allogeneic stem cell transplantation in liver diseases? As outlined above this concept has widely been proven in animal models of a great variety of different liver diseases, and indeed, finds increasing interest to progress into clinical translation.

1. Introduction

The role of hepatocyte-mediated liver regeneration during acute and chronic Liver progenitor cells (LPC) (or resident liver stem cells) are Group, Foundation for Liver Research, The Institute of Hepatology, London, UK. Only in recent years, research on all categories of stem cells in the thyroid SP cells isolated from adult muscle or liver contributed to tissue regeneration Clin Res Hepatol Gastroenterol () 35(10)–9. doi/

MSC have been shown to ameliorate liver fibrosis in mice and rats, which was likely due to the reduction of collagen synthesis and the induction of expression of metalloproteinases, the major players in matrix degradation and remodeling Parekkadan et al. Acute liver failure is a highly inflammatory response of the liver to exogenous toxic insults, which is characterized by parenchymal dysfunction leading to systemic organ failures due to the lack of metabolic homeostasis normally provided by the healthy liver.

Taking advantage of the anti-inflammatory, anti-apoptotic, and pro-proliferative features of MSC it has been shown in animal models that the cells attenuated acute liver failure by inhibition of inflammatory infiltration, reducing the rate of cell death, by increasing tissue recovery through stimulation of hepatocyte proliferation, and finally by augmenting survival rate Parekkadan et al. These encouraging results from animal studies prompted clinical application of MSC in chronic and acute liver failure 3.

However, so far there is only limited information available on the clinical outcome. In patients suffering from decompensated liver cirrhosis treatment with umbilical cord-derived MSC reduced ascites volume and improved liver function in the short-term range Kharaziha et al. Even if some clinical parameters might improve, the fate and long-term survival of the transplanted cells in the host liver, their mode of action, and finally safety in the long-term range have to be demonstrated.

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It is likely that depending on the etiology and pathophysiology of the liver disease to be treated MSC act differently according to their pleiotropic spectrum of action. Thus, the anti-inflammatory, anti-apoptotic, and pro-proliferative features of MSC might be favorable in cases of chronic inflammatory liver diseases but in addition a functional tissue replacement is warranted in cases where massive tissue loss has to be substituted to provide sufficient metabolic capacity like in acute liver failure and huge liver resections. Therefore, it is necessary to understand the impact of MSC both on the molecular and cellular level and their interactions with the host liver tissue under a given microenvironment as created by the diseased liver.

It might also be thought to use MSC in combination with primary human hepatocytes to either support hepatocyte function and moreover to minimize immunological rejection of the transplant in the short-term range taking advantage of the immunosuppressive features of MSC Stutchfield et al. This could help to bridge the patient to liver transplantation and even through the critical phase of acute liver failure until the host liver recovers from the acute insult. This is of high interest because this setting would enable allogeneic hepatocyte transplantation avoiding long-term immunosuppression with all the known undesired adverse effects.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Therapeutic potential of bone marrow-derived mesenchymal stem cells on experimental liver fibrosis. Human mesenchymal stem cells modulate allogeneic immune cell responses. Cancer stem cells in solid tumors. Tumor risk by tissue engineering: Stem cells in liver regeneration, fibrosis and cancer: Hepatocytes from non-hepatic adult stem cells.

A large animal noninjury model for study of human stem cell plasticity. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes.

Clinical and laboratory evaluation of patients with end-stage liver cell failure injected with bone marrow-derived hepatocyte-like cells. In vivo contribution of murine mesenchymal stem cells into multiple cell-types under minimal damage conditions. Functional characterization of serum-free cultured rat hepatocytes for downstream transplantation applications. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo.

Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers. Stem Cells 26, — Adipose tissue-derived mesenchymal stem cells as a source of human hepatocytes. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness.

Stem Cells 30, 33— Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines. Macrophage-derived wnt opposes notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Characterization of liver function in transdifferentiated hepatocytes. Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. Comparative phenotypic and molecular characterization of porcine mesenchymal stem cells from different sources for translational studies in a large animal model.

A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Efficient generation of human hepatocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep. Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Chondrogenic differentiation alters the immunosuppressive property of bone marrow-derived mesenchymal stem cells, and the effect is partially due to the upregulated expression of B7 molecules.

Stem Cells 25, — Falk Symposium , Vol. Rodent animal models for surrogate analysis of cell therapy in acute liver failure. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli.

Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. Liver regeneration and repair: The role of hepatocytes and oval cells in liver regeneration and repopulation.

Review of mesenchymal stem cells and tumors: Treatment of the Crigler-Najjar syndrome type I with hepatocyte transplantation. Mesenchymal stem cells share molecular signature with mesenchymal tumor cells and favor early tumor growth in syngeneic mice. Generation of liver disease-specific induced pluripotent stem cells along with efficient differentiation to functional hepatocyte-like cells. Ductular reactions in human liver: The role of bone marrow stem cells in liver regeneration.

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Evaluation of porcine mesenchymal stem cells for therapeutic use in human liver cancer. Pubmed Abstract Pubmed Full Text. Position-specific gene expression in the liver lobule is directed by the microenvironment and not by the previous cell differentiation state. Pluripotency and cellular reprogramming: Role of mesenchymal stromal cells in solid organ transplantation. In vitro differentiation of human umbilical cord blood-derived mesenchymal stem cells into hepatocyte-like cells.

Experimental conversion of liver to pancreas. Current status of hepatocyte transplantation. Transplanted human cord blood cells give rise to hepatocytes in engrafted mice. Bone marrow engraftment in a rodent model of chemical carcinogenesis but no role in the histogenesis of hepatocellular carcinoma. Hematopoietic stem cells convert into liver cells within days without fusion.

Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells.

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Pluripotency of mesenchymal stem cells derived from adult marrow. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. T cell responses to allogeneic human mesenchymal stem cells: Zonal expression of hepatocytic marker enzymes during liver repopulation. Dose- and time-dependent oval cell reaction in acetaminophen-induced murine liver injury.

Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24, — Immune regulation by mesenchymal stem cells derived from adult spleen and thymus. Bone marrow-derived cells fuse with hepatic oval cells but are not involved in hepatic tumorigenesis in the choline-deficient ethionine-supplemented diet rat model.

Observations on the fine structure of long-survived isolated hepatocytes inoculated into rat spleen. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Hepatocytic gene expression in cultured rat mesenchymal stem cells. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation.

HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. In vitro hepatic differentiation of human mesenchymal stem cells.