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.
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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.
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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.
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/domaine-solitude.com
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.
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.
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