# Developing a renewable and dissectible human liver for the study of HBV/HCV infection

> **NIH NIH DP2** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $483,000

## Abstract

Project Summary
HBV and HCV infections are among the leading causes of chronic liver disease worldwide. In the United States,
it is estimated that over 850 thousand people are currently infected with HBV and more than 2.4 million for HCV.
Despite the availability of highly effective HBV vaccine and HCV treatment, the mortality and the burden
associated with HBV and HCV are nevertheless increasing as individuals with existing infections advance into
more advanced stages including fibrosis, cirrhosis, and HCC. Moreover, HCV-infected patients, even though
cured of viremia, remain at a significantly elevated risk for advanced liver diseases. Due to their shared modes
of transmission and epidemiological features, HBV and HCV frequently coexist in patients in endemic areas or
among subjects at high risk of infection. Coinfection is usually more complex than monoinfection, leading to an
accelerated disease progression and complicated viral interaction for their treatment.
 Despite the severity of HBV and HCV infections, the mechanisms by which they lead to liver disease, of
how coinfection causes an increased severity and risk for complications, and of how HBV and HCV interact in
the liver of coinfected patients that may lead to reactivation of HBV upon the cure of HCV remains largely unclear.
This stems, in part, from the lack of relevant human models that recapitulate key disease phenotypes and permit
detailed mechanistic studies that could answer these questions.
 The primary research goal of this proposal is to establish a novel, high fidelity multicellular in vitro liver
model to address the aforementioned gaps. In this system, we plan to coculture human pluripotent stem cells
(hPSCs)-derived hepatocytes, hepatic stellate cells, macrophages, and endothelial cells. Unlike existing
traditional cell culture models, we propose to create an innovative three dimensional platform that mimics the
liver’s multicellularity and microenvironment, by culturing these four cell types in a configuration that resembles
the liver’s in vivo spatial organization, its hemodynamics, and its cell-cell interaction. To distinguish cell type-
specific responses, we will develop methods to purify individual cell types for downstream analysis.
 With this multicellular culture platform, we will pursue our long-range objectives, across which we capitalize
on the unique features of this novel platform to address questions that cannot be adequately answered with any
existing in vitro human-relevant system. These include the mechanisms of continued disease progression
following the cure of HCV infection, an accelerated disease progression with HBV/HCV coinfection, and the
interaction between HBV/HCV that leads to HBV reactivation following the cure of HCV infection (Aim 1). In Aim
2, we will combine hPSCs with gene editing to understand how genetic variants affect the course of disease and
treatment following HBV and HCV infection. These studies will not only provide new insights ...

## Key facts

- **NIH application ID:** 10497030
- **Project number:** 1DP2AI170515-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Xianfang Wu
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $483,000
- **Award type:** 1
- **Project period:** 2022-08-18 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10497030

## Citation

> US National Institutes of Health, RePORTER application 10497030, Developing a renewable and dissectible human liver for the study of HBV/HCV infection (1DP2AI170515-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10497030. Licensed CC0.

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