# A multi-modular approach for human pluripotent stem cell-based liver regeneration

> **NIH NIH R01** · BOSTON MEDICAL CENTER · 2020 · $555,521

## Abstract

PROJECT SUMMARY
Liver transplantation is currently the only treatment for acute and chronic liver failure. Given the shortage of
donor livers, hepatocyte transplantation is considered a potential treatment for liver diseases and a bridge for
patients awaiting liver transplantation, but its application has been hampered by a limited supply of hepatocytes.
Human induced pluripotent stem cell (hiPSC) could provide an unlimited supply of patient-specific hepatocytes
for cell replacement therapy. However, generation of hiPSC-derived hepatocyte like cells (HLCs) that
repopulate a damaged liver remains a challenge, and a major gap that this application targets. Obstacles
to HLC therapy include poor cell engraftment and insufficient maturation. Thus to fill this gap, we propose a multi-
modular approach that includes (1) a bi-cell therapy composed of HLCs and supportive endothelial cells (ECs),
both derived from hiPSCs (2) engineering HLCs with novel genetic circuit technology to promote their
engraftment and maturation and (3) engineering ECs to support HLC-mediated liver repair. This approach is
based on our long-standing expertise in the directed differentiation of PSCs to HLCs having pioneered the use
of BMP4 to induce hepatic specification, an approach now utilized widely in the field. We initially observed that
ECs were always associated with mouse ESC-derived HLC clusters, and showed that ECs function as a niche
to repress Wnt and Notch signaling to promote HLC specification. Recently, we discovered that this EC
supportive function is dependent on activation of VEGFR2. Consistent with our data, it has been shown that a
VEGFA-VEGFR2 axis activates sinusoidal ECs in injured mouse livers to induce the expression of factors such
as WNT2 and HGF that trigger hepatocyte proliferation. Similarly, WNT2 and WNT9b secreted by sinusoidal
ECs were shown to induce hepatocyte proliferation following partial hepatectomy. Thus, bi-cell therapy with ECs
represents a potential strategy to overcome the obstacles of HLC therapies. In addition, we will enhance EC
supportive functions through modulation of VEGFR2 and downstream factors such as HGF, WNT2 and WNT9b.
In parallel, we will engineer HLCs to activate mitogen receptors cMET, EGFR and IL6R and express transcription
factors (ATF5, PROX1, CEBPA) that are critical for liver development, regeneration and the maturation of
reprogrammed fibroblast-derived HLCs. We will test that these pathways and TFs accelerate HLC engraftment
and maturation following bi-cell therapy. This proposal may have major clinical implications as VEGFR2,
cMET, EGFR and IL6R will be activated in vivo using the clinically safe lipid nanoparticle-complexed non-
integrative nucleoside-modified mRNA (mRNA-LNP). Our preliminary data indicate that mRNA-LNP encoding
HGF, EGF and IL6 significantly improve HLC survival after transplantation into liver injury mouse models. Our
central hypothesis is thus: a bi-cell therapy with HLCs and ECs engineered t...

## Key facts

- **NIH application ID:** 10122136
- **Project number:** 1R01DK124361-01A1
- **Recipient organization:** BOSTON MEDICAL CENTER
- **Principal Investigator:** VALERIE B GOUON-EVANS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $555,521
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10122136

## Citation

> US National Institutes of Health, RePORTER application 10122136, A multi-modular approach for human pluripotent stem cell-based liver regeneration (1R01DK124361-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10122136. Licensed CC0.

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