# Lung MSC regulate angiogenesis and repair during fibrosis

> **NIH NIH R01** · NATIONAL JEWISH HEALTH · 2020 · $611,477

## Abstract

SUMMARY
Chronic lung disease, including fibrosis, is the fourth leading cause of mortality worldwide. Pulmonary fibrosis
(PF) is a debilitating pathology that impedes overall tissue function. A common comorbidity in fibrosis is
vasculopathy, characterized by remodeling and loss of microvessels, which substantially worsens prognosis
and limits survival, most current therapeutic strategies being largely palliative. The relevance of
neovascularization to the pathophysiology of fibrosis has never been resolved as conflicting evidence depicts
angiogenesis as both, reparative or pathologic. Therefore, we must begin to understand and model the
underlying pathobiology of PVD, alone and with fibrosis, to define cell interactions necessary to maintain
normal function and promote repair. We have identified a novel model of vasculopathy dependent on the
function of adult pulmonary resident mesenchymal pericyte progenitors (ABCG2pos MPC). The MPC regulate
microvascular function during tissue homeostasis and the extent of vasculopathy in lung tissue. Therefore, lung
MPC is a previously unstudied target that should be exploited to identify new mechanisms and therapeutic
targets relevant to the pathobiology of PVD associated with fibrosis. A premise for this proposal is that that
ABCG2pos lung MPC are key constituents of the microvascular niche, as such, disrupted ABCG2pos MPC
differentiation accounts in part for the deregulation of microvessel function and remodeling associated with
PVD and exacerbation of fibrosis. We hypothesize that ABCG2posMPC regulated loss of microvessel function
drives the development of persistent vasculopathy, which exacerbates the onset and development of fibrosis in
the lung. In this proposal, we will test that activation of Wnt/β-catenin signaling in MPC exacerbates the onset
and persistence of fibrosis in vivo and in vitro. We hypothesize that MPC derived DKK1 modulates MPC-MVEC
interactions via regulation of direct cell - cell communication and paracrine effects on MVEC function. We will
also test that modulation of DKK1 expression and signaling activity in ABCG2pos MPC will restore
microvascular function and attenuate fibrosis. Both in vivo and in vitro we will repurpose drugs currently
approved and utilized as chemotherapeutic agents with WT, IPF, PVD MPC & murine models. Successful
completion of the proposed studies will define the therapeutic potential for targeting the Dkk1/Lrp6 signaling
pathway identified in MPC to restore microvessel function and decrease fibrotic remodeling. We are poised to
complete these studies with combined expertise and tools specific to our group.

## Key facts

- **NIH application ID:** 9928488
- **Project number:** 5R01HL136449-03
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** SUSAN M MAJKA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $611,477
- **Award type:** 5
- **Project period:** 2018-02-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928488

## Citation

> US National Institutes of Health, RePORTER application 9928488, Lung MSC regulate angiogenesis and repair during fibrosis (5R01HL136449-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928488. Licensed CC0.

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