Anatomy, Physiology and Human Biology

Stem Cell Mechanobiology

Further Information

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Yu Suk Choi 

Dr Yu Suk Choi

The School of Anatomy, Physiology and Human Biology offers a diverse range of student research topics.

My research focus is in controlling stem cell fate by providing different microenvironments. The fate of stem cells were thought to primarily dictated by biochemical signals including cytokines and growth factors for decades, however, more recent data suggested stem cells also responded to their neighbouring cells and extracellular matrices (ECMs). Previously, I have shown that stem cells from fat (adipose-derived stem cells – ASCs) were able to feel/sense and respond (mechanosense) to matrices mimicked stiffness of brain, skeletal muscle, and bone and committed to differentiate into those tissue lineages, respectively. Intracellularly, stem cells transduce these biophysical/mechanical signals into biochemical signals from cell membrane to nucleus and this process is called mechanotransduction. Our group aims to study how mechanical cues (especially stiffness) control stem cells by focusing on 3 areas: 1) investigating intracellular mechanism how stem cells respond to ECM mechanical cues, 2) developing bio-inspired ECM (2D and 3D biomaterials) as platforms to control stem cell fate, 3) programming stem cells to be used in stem cell therapy, tissue engineering and regenerative medicine.

Mechanosensing-driven stem cell differentiation on high-throughput stiffness gradient hydrogel with micropatterns

Project Outline

Adipose-derived stem cells (ASC) which could be isolated from patient by minimal invasive procedure, liposuction, has known to be capable of rapid growth (regenerating large volume of tissue) and skeletal muscle or fat differentiation. Previously, osteogenic (bone) and adipogenic (fat) differentiation has been heavily relied on biochemical methods, however, the efficiency remains questionable for large volume regeneration. More recently, it has been shown that surrounding extracellular matrix (ECM) could also influence the fate of stem cells. Particularly in respect to stiffness (one of the mechanical properties of ECM), my previous studies showed that ASCs were able to ‘feel’ and/or ‘sense’ how stiff the underneath was when cultured on hydrogels that mimicked stiffness of bone or adipose tissues without biochemical induction and be differentiated into bone or fat cells, respectively. Others also showed that ECM protein composition played significant role in stem cell differentiation as well as geometry, which will decide cell shape and size. Their combinatorial (biochemical and biomechanical) induction has yet to be examined. The aim of this project is to develop a high-throughput screening platform to examine the most synergistic combinations of biochemical and biomechanical induction for bone or fat cell differentiation. For high-throughput screening, stiffness gradient hydrogel (stiffness ranges from fat-like soft to bone-like hard) was fabricated using two-layer hydrogel polymerization technique. Micro-contact printing technique will be used to stamp different ECM proteins (e.g. collagen) with different shapes and sizes on the stiffness gradient gel to test best combination of stiffness, ECM protein composition and shape/size. To summarize, this platform will allow us to test stem cell differentiation with 6 stiffness, 6 ECM proteins, 6 shape/size, and 6 biochemical induction media by 6 repeats in one 6-well plate. This high-throughput screening platform will ‘speed up’ tissue engineering approach using stem cells to regenerate bone and fat tissues.

Project is suitable for

Honours, Masters and PhD

Supervisors

Dr Yu Suk Choi

Other Supervisors

Associate Professor Adam Engler at University of California, San Diego (UCSD)

Essential qualifications

For Honours: An appropriate undergraduate degree with a minimum weighted average of 65% in the level 3 subjects that comprise the relevant major, from an approved institution. Applicants will be assessed on a case-by-case basis.

For Masters or PhD : An appropriate Honours degree or equivalent research experience from an approved institution. Applicants will be assessed on a case-by-case basis.

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Role of YAP/TAZ in stem cell mechanotransduction, differentiation, and migration

Project Outline

There are several pathways and key signaling molecules suggested in mechanotransduction. Most of suggested pathways involve focal adhesion with extracellular binding of integrin to ECM protein as a starting point and intracellular interaction of beta unit of integrin to actin-myosin through focal adhesion kinase (FAK), talin, and vinculin binding. Intracellular forces generated by different matrix stiffness will decide localization (cytoplasmic vs. nucleic) of YAP/TAZ (transcriptional coactivator in Hippo pathway), which will control transcriptional level as a final step. Bone marrow-derived stem cells exhibited cytoplasmic localization of YAP/TAZ on soft hydrogel (fat-like stiffness) but YAP/TAZ was localized in nuclei on stiffer hydrogel (bone-like stiffness). Differentiations into fat and bone lineages were also observed and YAP/TAZ overexpression or knockdown cells altered mechanical induction (no bone differentiation on bone-like stiffness when YAP/TAZ knock-downed). Most studies with YAP/TAZ assumed it as a downstream of mechanosensing but more recent results (YAP/TAZ changes integrin expression profile in cancer research) suggest that YAP/TAZ may have feedback effect to ‘feeling’ or YAP/TAZ act as upstream of ‘feeling’ as well. In this project, we aim to investigate the effect of YAP/TAZ on mechanosensing (once considered as upstream of YAP/TAZ) in the context of intracellular force generation (direct response from extracellular stiffness), migration, and differentiation.  

Project is suitable for

Honours, Masters and PhD

Supervisors

Dr Yu Suk Choi

Other Supervisors

Prof. Kun-Liang Guan and Dr. Henry Park at UCSD)

Essential qualifications

For Honours: An appropriate undergraduate degree with a minimum weighted average of 65% in the level 3 subjects that comprise the relevant major, from an approved institution. Applicants will be assessed on a case-by-case basis.

For Masters or PhD : An appropriate Honours degree or equivalent research experience from an approved institution. Applicants will be assessed on a case-by-case basis.

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Mechanotransduction driven cardiac differentiation of stem cells

Project Outline

After myocardial infarct (MI), the microenvironments of the damaged heart muscle become stiffer than healthy cardiac muscle. This stiffened extracellular matrix (ECM) may misdirect stem cells to differentiate into other lineage cell types than cardiomyocytes when injected into scarred area. In this project, we will fabricate polymer hydrogels to mimic heart tissue stiffness at various stages (healthy vs. diseased after MI) and study stem cell behaviours including proliferation and cardiac differentiation. This reductionist's approach will enhance our understanding how stem cell - ECM stiffness interact in heart tissue with or without MI and give us better insight to make natural ECM mimicked biomaterials for cardiac regeneration.    

Project is suitable for

Honours, Masters and PhD

Supervisors

Dr Yu Suk Choi

Essential qualifications

For Honours: An appropriate undergraduate degree with a minimum weighted average of 65% in the level 3 subjects that comprise the relevant major, from an approved institution. Applicants will be assessed on a case-by-case basis.

For Masters or PhD : An appropriate Honours degree or equivalent research experience from an approved institution. Applicants will be assessed on a case-by-case basis.

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N-cadherin-mediated cell-cell and integrin-mediated cell-ECM mechanotransduction in heart  

Project Outline

The human heart, a mechanically dynamic tissue, pumps out ~5L of blood/ minute. At tissue level, its mechanical function has been widely studied, but little is known at cellular level how cardiac muscle cells mechanically coordinate their beating with neighboring cells or how mechanical extracellular stimuli dictate cardiac muscle cell behavior. One cardiac muscle cell in vivo may make three principal connections with its surroundings (i) cell-ECM adhesion via integrin-mediated focal adhesion, (ii) cell-cell adhesion via N-cadherin, and (iii) cell-cell gap junction with ion channels including the calcium channel. In disease models in particular, not only biochemical signaling changes but also the mechanical environment alters the cell’s behavior via these 3 main connections. For example after myocardial infarction (MI), excessive deposition of collagen causes greater ECM stiffness, which may alter focal adhesion complex / actinin (i.e. the Z-band – an important structure bearing contractile forces) and disrupt cytoskeletal structure resulting in loss of contraction and alteration of cell-cell interaction via N-cadherin. This project aims to address how these 3 main connections (N-cadherin, focal adhesion, and gap junction) control the cardiomyocyte’s function in disease. Three specific aims address 1) the effects of ECM stiffness on cardiomyocyte function; cell-ECM mechanotransduction, 2) mechanosensitivity of cardiomyocyte via N-cadherin; cell-cell mechanotransduction, and 3) ion handling capacity, especially calcium which is the main driving force for cardiomyocyte contraction, examining different cell-cell / cell-ECM situations.  

Project is suitable for

Honours, Masters and PhD

Supervisors

Dr Yu Suk Choi

Essential qualifications

For Honours: An appropriate undergraduate degree with a minimum weighted average of 65% in the level 3 subjects that comprise the relevant major, from an approved institution. Applicants will be assessed on a case-by-case basis.

For Masters or PhD : An appropriate Honours degree or equivalent research experience from an approved institution. Applicants will be assessed on a case-by-case basis.

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Stem cell mechanotransduction in osteochondral tissue engineering

Project Outline

The causes associated with osteochondral defects vary from natural wearing to trauma related injuries. With ageing, the natural degradation or wearing of the cartilage often leads to osteoarthritis. Tissue engineering approaches have emerged in last two decades to regenerate damaged tissues using biomaterials, stem cells, and supplementary biochemical. One of the challenges in osteochondral tissue engineering was to fabricate or mimic bilayer structures at the border of articular cartilage and bone, which can further divided into superficial zone, middle zone, deep zone/calcified cartilage, and subchondral bone. As ECM components per zone from cartilage to bone vary, their compressive modulus (stiffness) show huge ranges in order of magnitude from 79KPa, 2.1MPa, 320MPa, and 5.7GPa where cells mechanosense very differently.  Here, we aim to develop biomaterials that mimic stiffness step gradient to examine how stem cell mechanotransduction plays role in osteochondral tissue engineering. Stiffness step gradient hydrogel will be fabricated using two-layer hydrogel polymerization technique modified from my previous research. Bone marrow-derived stem cells and adipose-derived stem cells will be tested their chondro- and osteo-genic capacity on biomaterials and their mechanotransduction will also be studied. Once this reductionist approach provide answers in mechanosensing of stem cells per stiffness, biochemical component of ECM can be added up to investigate synergistical effect of biomechanical (stiffness) and biochemical (ECM components) in osteochondral tissue engineering. To summarize, this study will enhance our understanding in mechanical influence at cellular level in both chondro- and osteo-genic regeneration and also provide deep insight for biomaterials fabrication in osteochondral tissue engineering.    

Project is suitable for

Honours, Masters and PhD

Supervisors

Dr Yu Suk Choi

Essential qualifications

For Honours: An appropriate undergraduate degree with a minimum weighted average of 65% in the level 3 subjects that comprise the relevant major, from an approved institution. Applicants will be assessed on a case-by-case basis.

For Masters or PhD : An appropriate Honours degree or equivalent research experience from an approved institution. Applicants will be assessed on a case-by-case basis.

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