Lymphedema is the accumulation of lymphatic fluid in the interstitial spaces caused by a defect in the lymphatic vascular system. It is marked by edema, chronic inflammation, and fibrosis, which can lead to painful, disfiguring abnormalities and serious infection. While primary lymphedema occurs infrequently on a hereditary or idiopathic basis, secondary lymphedema is common worldwide, primarily due to infectious disease or radical surgery and radiotherapy for cancer. Despite a continuous increase in the incidence of lymphedema, current therapeutic options are limited to palliative surgical and conservative techniques. Recent progress toward understanding the molecular mechanisms of new lymphatic vessel growth has shed new light on the treatment of lymphedema. Growth factor therapy has yet to show clear clinical benefits in treatment of diseases characterized by deficient arterial or venous vasculature; using a similar strategy to approach lymphedema may face similar hurdles. Recent groundbreaking studies have demonstrated that introduction of pluripotency-associated transcription factors can reprogram somatic cells into embryonic stem (ES)-like cells, referred to as induced pluripotent stem cells (iPSCs). The discovery of iPSCs has presented the opportunity for ES cell-equivalent stem cells to be used therapeutically without concerns about immunologic incompatibility and ethical controversy. Recently, we have developed protocols to efficiently differentiate human iPSCs and ESCs into lymphatic endothelial cell (LEC) lineages. We therefore propose to study the therapeutic effects of hPSC-derived LECs, and their bioengineered derivatives with extracellular matrix-mimicking nanomatrix, on experimental lymphedema.
In aim 1, we will develop a novel clinically compatible method to differentiate hPSCs into the lymphatic endothelial lineage and isolate pure hPSC-LECs.
In aim 2, we will engineer hPSC-derived LECs with peptide amphiphile-based nanomatrix gel for enhancing cell survival and function.
In aim 3, we will determine the effects of hPSC-derived LECs and their bioengineered constructs on experimental lymphedema. We anticipate that the results of the proposed experiments will yield new insight into the role of novel stem cell-based therapy for treating lymphedema.

Public Health Relevance

We have developed methods to differentiate human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, into the lymphatic endothelial cell (LEC) lineage. In this proposal, we will seek to investigate the therapeutic effects and lymphatic neovascularization effects of hPSC-derived LECs and their bioengineered derivatives on experimental lymphedema. Ultimately this study aims to develop effective hPSC-based therapy for treatment of human lymphedema.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127759-03
Application #
9310409
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tolunay, Eser
Project Start
2015-07-01
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Park, Misun; Yoon, Young Sup (2018) Cardiac Regeneration with Human Pluripotent Stem Cell-Derived Cardiomyocytes. Korean Circ J 48:974-988
Lee, Shin-Jeong; Kim, Kyung Hee; Yoon, Young-Sup (2018) Generation of Human Pluripotent Stem Cell-derived Endothelial Cells and Their Therapeutic Utility. Curr Cardiol Rep 20:45
Lee, Shin-Jeong; Sohn, Young-Doug; Andukuri, Adinarayana et al. (2017) Enhanced Therapeutic and Long-Term Dynamic Vascularization Effects of Human Pluripotent Stem Cell-Derived Endothelial Cells Encapsulated in a Nanomatrix Gel. Circulation 136:1939-1954
Lee, Sangho; Kim, Jin Eyun; Johnson, Brandon Al et al. (2017) Direct reprogramming into endothelial cells: a new source for vascular regeneration. Regen Med 12:317-320
Lee, Sangho; Park, Changwon; Han, Ji Woong et al. (2017) Direct Reprogramming of Human Dermal Fibroblasts Into Endothelial Cells Using ER71/ETV2. Circ Res 120:848-861
Ban, Kiwon; Bae, Seongho; Yoon, Young-Sup (2017) Current Strategies and Challenges for Purification of Cardiomyocytes Derived from Human Pluripotent Stem Cells. Theranostics 7:2067-2077
Kim, Sung-Whan; Jin, Hong Lian; Kang, Seok-Min et al. (2016) Therapeutic effects of late outgrowth endothelial progenitor cells or mesenchymal stem cells derived from human umbilical cord blood on infarct repair. Int J Cardiol 203:498-507
Han, Ji Woong; Choi, Dabin; Lee, Min Young et al. (2016) Bone Marrow-Derived Mesenchymal Stem Cells Improve Diabetic Neuropathy by Direct Modulation of Both Angiogenesis and Myelination in Peripheral Nerves. Cell Transplant 25:313-26
Lee, Sangho; Valmikinathan, Chandra M; Byun, Jaemin et al. (2015) Enhanced therapeutic neovascularization by CD31-expressing cells and embryonic stem cell-derived endothelial cells engineered with chitosan hydrogel containing VEGF-releasing microtubes. Biomaterials 63:158-67
Ban, Kiwon; Wile, Brian; Cho, Kyu-Won et al. (2015) Non-genetic Purification of Ventricular Cardiomyocytes from Differentiating Embryonic Stem Cells through Molecular Beacons Targeting IRX-4. Stem Cell Reports 5:1239-1249

Showing the most recent 10 out of 11 publications