Review articleThe role of extracellular matrix on liver stem cell fate: A dynamic relationship in health and disease
Introduction
The stem cell niche is a specific and dynamic microenvironment in which many inputs such as signals departing from blood vessels, neural and supportive cells, as well as secreted factors, and extracellular matrix (ECM) components regulate stem cell behavior. These multiple signals with a physical, electrical, structural or biochemical nature are responsible for supporting stem cell properties.
In the last two decades, the role and importance of the ECM in cell biology has considerably increased, and currently, the ECM is recognized as an active entity composed of a variety of proteins and other molecules (Akhmanova et al., 2015). Besides, the structural, chemical and functional diversity of ECM components confers distinct biomechanical and biochemical properties to the ECM, providing a specific composition to the matrix, strictly correlated with the tissue, and sometimes species, of origin. In the liver, the extrahepatic stem cell niches are located in the peripheral or peribiliary glands inside the walls of the bile ducts, while the intrahepatic stem cell niches are found on the ductal plates of fetal livers and the Canals of Hering in the postnatal livers (Schmelzer et al., 2007). Although the major structural components of liver's ECM are collagens (COL) and fibronectin (FN), the matrix of bile ductules, where the progenitor cells reside, is mainly composed of COL IV and laminin (LN) (Terada and Nakanuma, 1994; Yasoshima et al., 2000).
The liver is known for its unique regenerative capability. The support of stem cell behavior provided by the stem cell niche helps maintain their quiescent state in homeostasis and regulates their self-renewal, expansion, and differentiation after activation. Following tissue injury, the surrounding microenvironment promotes self-renewal and differentiation of stem cells by activating and sending numerous signals. Moreover, the secretion of diverse growth factors (GF) such as TGF-α, EGF, FGF, and HGF play an essential role in liver development, health, and disease. The ECM is also a reservoir of GF and bioactive molecules by regulating their diffusion and availability (Hynes, 2009; Wilgus, 2012). It is constituted by adhesive molecules, notch signaling proteins, and proteoglycans which can bind and modulate GF activity (Lee et al., 2011).
Several authors have tried to determine which factors, signals or conditions control the fate choice of hepatic stem/progenitor cells to differentiate towards a specific cell type. This review provides an in-depth summary of the most recent findings on the role of hepatic ECM in liver stem cell behavior.
Section snippets
Composition and function of stem cell niches in solid organs
In 1978, Raymond Schofield proposed that stem cells resided in specific locations called niches, which provided a complex multifactorial microenvironment (Schofield, 1978). Today, we can determine that a stem cell niche is an accurate and complex microenvironment within a specific anatomic location. It comprises cellular and acellular elements that interact with local and systemic signals for the regulation of the stem cell function (Kordes and Haussinger, 2013; Mohyeldin et al., 2010; Scadden,
Liver development
Hepatic development and organization begins by the third week of gestation and continues until the postnatal stage. The anterior portion of the hepatic diverticulum forms the intrahepatic biliary tree and the liver, whereas the posterior portion gives rise to the extrahepatic bile ducts and the gallbladder (Zorn, 2008).
From definitive endoderm, hepatocytes are originated during embryonic development after hepatic competence acquisition by ventral foregut endoderm and specification of those
Liver stem cell niches
The human hepatic stem cells are located in the ductal plates of the fetal and neonatal livers, and in the Canals of Hering in pediatric and adult livers (Kordes and Haussinger, 2013; Kuwahara et al., 2008; Saxena and Theise, 2004; Schmelzer et al., 2007; Stachelscheid et al., 2009; Zhang et al., 2008; Zhou et al., 2007). These cells constitute approximately 0.5–2% of the parenchyma and have a size that ranges between 7 and 10 μm in diameter with a high nuclear-cytoplasm ratio. They express
The interaction between ECM and hepatic stem cells
The process of ECM renovation is a complex but remarkably synchronized procedure resulting from the equilibrium among production, secretion, degradation (Lu et al., 2011). Although ECM comprises less than 3% in a healthy liver section (Gressner, 1992), and minimal modification on the ECM has a direct consequence in hepatic functions (Bedossa and Paradis, 2003).
The principal structural components of the liver ECM are COL and FN. COL I and III are expressed in the portal stroma, space of Disse,
Conclusion
It is well known that the liver is an organ with a remarkable regenerative capacity. Part of this regenerative ability is possible due to the synchronous proliferation of stem cells and ECM remodeling in the stem cell niche, which provides a complex multifactorial microenvironment where many inputs regulate stem/progenitor cell behavior.
Traditionally, decades ago, the liver ECM was considered to be an inert cell growth substrate. However, due to the developments made in the last decades, it is
Conflicts of interest
All the authors have read and understood the Journal of Differentiation policy on declaration of interests and declare that we have no competing interests.
Acknowledgments
This work was supported by Gobierno de Aragón and Fondo Social Europeo through a predoctoral Fellowship DGA C066/2014 (P. S-A), Instituto de Salud Carlos III, through a predoctoral fellowship i-PFIS IFI15/00158 (I. P-P). N. S-R was supported by a POCTEFA/Refbio II research grant. PMB was supported with the project PI15/00563 from Instituto de Salud Carlos III, Spain.
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These authors contributed equally to this review.