Abstract
Recent studies have discovered aging-associated changes of adult stem cells in various tissues and organs, which potentially contribute to the organismal aging. However, aging-associated changes of liver progenitor cells (LPCs) remain elusive. Employing young (2-month-old) and old (24-month-old) mice, we found diverse novel alterations in LPC activation during aging. LPCs in young mice could be activated and proliferate upon liver injury, whereas the counterparts in old mice failed to respond and proliferate, leading to the impaired liver regeneration. Surprisingly, isolated LPCs from young and old mice did not exhibit significant difference in their clonogenic and proliferative capacity. Later, we uncovered that the decreased activation and proliferation of LPCs were due to excessive reactive oxygen species produced by neutrophils infiltrated into niche, which was resulted from chemokine production from activated hepatic stellate cells during aging. This study demonstrates aging-associated changes in LPC activation and reveals critical roles for the stem cell niche, including neutrophils and hepatic stellate cells, in the negative regulation of LPCs during aging.
Highlights
Organismal aging is a process of functional decline due to histologic and biochemical changes in tissues and organ systems with the passage of time [1]
We uncovered that the decreased activation and proliferation of liver progenitor cells (LPCs) were due to excessive reactive oxygen species produced by neutrophils infiltrated into niche, which was resulted from chemokine production from activated hepatic stellate cells during aging
In this study, taking advantage of a well-established murine LPC activation model, we investigated the alterations in LPC functionality and liver regeneration during aging, and uncovered that the decreased activation and proliferation of LPCs were due to excessive reactive oxygen species (ROS) produced by neutrophils infiltrated into niche, which was resulted from chemokine production from activated hepatic stellate cells during aging
Summary
Organismal aging is a process of functional decline due to histologic and biochemical changes in tissues and organ systems with the passage of time [1]. Like all the other organs, there are structural and functional changes in the liver during aging, including reduction in organ size, increased hepatic dense body compartment, declined capacities in Phase I metabolism of certain drugs, altered expression of a variety of proteins, and diminished hepatobiliary functions [2]. A decrease in regenerative capacity in aging liver has been observed in old patients who had severe viral and toxic injury [3]. Studies on liver transplantation in human patients showed lower graft and recipient survival if donor was in advanced age [4]. Similar results were observed after liver transplantation in rats [5]. Investigating the mechanisms of declined regeneration in liver is critical to understand age-associated hepatic pathologies and diseases
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