Stem cells and cardiovascular development

The genetic basis of cardiovascular development and disease

During embryonic development, undifferentiated cells are prompted to make ‘decisions’ that ultimately direct them to becoming one tissue type or another.

The mechanisms that control genes and gene networks responsible for driving these decisions during cardiovascular differentiation are the focus of Dr Palpant’s research group.

“Information about changes in a cell’s environment are communicated through signalling pathways that are complex and very carefully orchestrated. This information is transmitted to the nucleus in order to guide cell identity and fate.” said Dr Palpant.

“The transcriptome – or collection of RNA readouts encoding information controlling a cell’s identity – changes through development and provides a signature of the function and fate of specific cell types.”

Latest publication

Single-Cell Transcriptomic Analysis of Cardiac Differentiation from Human PSCs Reveals HOPX-Dependent Cardiomyocyte Maturation

Dr Palpant and colleagues have published the most in-depth study of exactly how human stem cells can be turned into heart cells. The work involved measuring changes in gene activity in tens of thousands of individual cells as they move through the stages of heart development.

Unlike those tissues, the heart does not have the capacity for self-repair after damage (such as a heart attack). This is one reason why heart disease is the leading cause of death worldwide. This research may help us find ways to repair the heart in the future. ​Read more

Research overview

Part of Dr Palpant’s interest is in analysing differences in how the genome is organised and translates cell-specific information in the nucleus as it differentiates into different lineages or across time. Understanding these changes has revealed approaches to identifying functionally distinct parts of the genome that define key control DNA elements that guide a cell through changes in cell state.

“Changes in the organisation of the genome and transcriptome in the nucleus translate to changes in the fate of cells,” he said.  

One of the major challenges in the field has been the derivation of cell subtypes – atrial vs ventricular heart cells, and generating cells similar to those that comprise normal organ development. Understanding the mechanisms of cell lineage decisions will help researchers control differentiation into pure, functional cell subtypes or tissues.

“We’re studying cardiovascular development and disease processes in the lab, from the genomic level to tissue-level engineering,” said Dr Palpant.

This offers the potential to develop approaches for cell therapeutic applications, model diseases, discover novel drugs, and devise other translational outcomes to address cardiovascular disease, the number-one killer in the world.

Research projects

Genetic regulation of cardiovascular development

We use human pluripotent stem cells coupled with genomics approaches including single cell sequencing, analysis of transcription factor binding, and chromatin dynamics, to study how cells navigate fate choices during cardiac and vascular differentiation. We couple these approaches with genome edited cell lines to study how loss of individual genes or perturbation of gene networks impact cell states to understand mechanisms governing cell differentiation.

Developing novel differentiation protocols

The capacity to generate therapeutically relevant cell types requires precise control of signaling pathways and gene networks needed to direct cells into function derivatives. We use developmental biology to inform our protocol design to guide cells into cardiac and vascular subtypes with high purity.

Stem cells in translation

We are collaborating with colleagues including Dr. John Fraser at The Prince Charles Hospital to use stem cells, animal models, mechanical assist devices, and ex vivo organ perfusion systems to study how we can improve the functionality and viability of transplantable organs.

Disease modelling

Functional cell types derived from human pluripotent stem cells are a significant advance for studying complex environment/gene interactions in disease and modelling congenital and acquired disease states. This provides a powerful approach to study these pathologies and discover novel drugs. We are using hPSCs to develop models of cardiovascular disease with a particular focus on ischemic and diabetic cardiomyopathy.

Research training opportunities

Research title: Mechanisms underlying cardiovascular cell lineage decisions

Summary of research interests: In recent years, bioengineering and biotechnology approaches have emerged for studying complex developmental processes with high resolution and precision. Understanding how cell fate choices are controlled during development will help us delve into the basis of congenital and acquired cardiovascular diseases and enable us to make high purity cell types from stem cells that can be used for therapeutic applications. My lab aims to understand how cell fate choices are made during the early stages of cardiovascular development. We use human pluripotent stem cells coupled with advanced techniques in bioengineering, genome engineering and deep sequencing to dissect the molecular basis of lineage choices.

Traineeships, honours and PhD projects include

  • Study the genetic basis of cardiovascular lineage choices using genomics (RNA-seq/ChIP-seq) and genome edited stem cell lines.
  • Use single cell level gene network analysis to identify mechanisms controlling cardiovascular fates from pluripotency. Identify novel small molecules that manipulate these gene networks to better control lineage choices during differentiation.
  • Determine the role of genetic regulators of cardiovascular disease using gain and loss of function zebrafish and stem cell lines.

Contact: Dr Nathan Palpant

+61 7 3346 2054
n.palpant@imb.uq.edu.au


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Engagement and impact

Research using human pluripotent stem cells has opened significant opportunities in a number of fields including the study of early human development, developing models of human disease to discover new drugs, generating cell types that could help regenerate injured organs or tissues, and developing complex vascularized functional tissues to understand human physiology.

My lab bridges a wide range of applications with the intent of addressing the single most significant cause of death worldwide, cardiovascular disease.

We are working with collaborators around the world to make an impact on human health using the most current technologies in computational genomics, genome editing, stem cell differentiation, animal modelling, and drug discovery.

Partners and collaborators

Dr Palpant collaborates widely both in Australia and internationally.

Australian collaborators include:

  • Mat Francois, Ben Hogan and Kelly Smith from IMB's Genomics of Development and Disease Division in cardiovascular development.
  • James Hudson (UQ, SBMS) with cardiac bioengineering expertise, Mikael Boden (UQ, SCMB) with expertise in epigenetics, and Joseph Powell (IMB) with computational genomics and single cell expertise.
  • Dr John Fraser (The Prince Charles Hospital, Brisbane) is a key clinical collaborator for the lab’s translational research.  
  • Collaborators across the network of Australian stem cell scientists, Stem Cells Australia, including Richard Harvey and Cath Suter (VCCRI) and Patrick Tam (CMRI). 

International collaborations include:

  • Yuliang Wang from the Computational Biology Program at the Department of Biomedical Engineering, Oregon Health Sciences University, USA in Analysis of chromatin dynamics and gene expression in mesoderm progenitor populations.
  • Jonathan Epstein, Cell and Developmental Biology, University of Pennsylvania, USA in Analysis of HOPX in developmental hematopoiesis.
  • Irwin Bernstein, of the Fred Hutchinson Cancer Research Center, USA, in Analysis of hematopoietic potential from hESC-derived endothelial populations.
  • Hannele Ruohola Baker, Institute for Stem Cell and Regenerative Medicine, University of Washington, analysis of genetic regulators of cardiovascular development.
     

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Dr Nathan Palpant

Dr Nathan Palpant

Group Leader, Genomics of Development and Disease Division, IMB
Co-Director, Queensland Facility for Advanced Genome Editing, IMB

  +61 7 3346 2054  
  n.palpant@imb.uq.edu.au
  IMB Researcher Profile
  Centre for Cardiac and Vascular Biology
  Queensland Facility for Advanced Genome Editing


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  Group Leader

  • Dr Nathan Palpant

    Group Leader, Genomics of Development and Disease Division
    Senior Research Fellow - GL
    Institute for Molecular Bioscience

  Researchers

  • Mr Han Chiu

    Research Assistant
    Institute for Molecular Bioscience
  • Dr Di Xia

    Senior Research Assistant
    Institute for Molecular Bioscience
  • Dr Meredith Redd

    Research Officer
    Institute for Molecular Bioscience

  Students