Zoldan Lab

Engineering Stem Cell Microenvironments

Dr. Zoldan is awarded NIH Trailblazer Grant

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On the wall of Janet Zoldan’s lab, which is teeming with enthusiastic students, is a poster with ZOLDAN LAB in capital letters printed across the top. Underneath it lies a short, curious statement: Stem Cells Are Like Pokèmon.

“Stem cells can become any cell type just as Pokémon can evolve into more advanced Pokémon,” said Zoldan, an assistant professor in the Department of Biomedical Engineering in the Cockrell School of Engineering. When exposed to specific physical or chemical signals, or cues, a stem cell can become a specialized cell. This process is also known as differentiation.

Her work on engineering the fate of human-induced pluripotent stem cells (iPSCs) — adult cells that can be converted to embryonic-like stem cells and used to treat everything from diabetes to heart failure — earned her recognition this year from the National Institutes of Health (NIH) with the Trailblazer Award, which is given annually by NIH’s National Institute of Biomedical Imaging and Bioengineering to select early-stage investigators exploring new areas of biomedical research. Zoldan is the first UT Austin faculty member to receive the award.

Through a novel biomedical engineering process, Zoldan is looking at how iPSCs “evolve” into the cells needed to form new blood vessels and how near-infrared light can be utilized to precisely control this process. The Trailblazer Award will allow her to continue her work and develop new stem cell therapies for patients suffering from cardiovascular diseases.

“We are trying to develop a microenvironment whereby patient-specific stem cells can be coerced to form blood vessels via light activation,” Zoldan said. “In simple terms, we are painting vessels with light.”

Nima Publishes in Trends in Molecular Medicine

Congratulations to our new postdoc, Dr. Nima Momtahan, who had his opinion article on the role of reactive oxygen species in cardiac maturation published in Trends in Molecular Medicine. The article is linked here and the abstract is listed below:

Recent advances in developmental biology and biomedical engineering have significantly improved the efficiency and purity of cardiomyocytes (CMs) generated from pluripotent stem cells (PSCs). Regardless of the protocol used to derive CMs, these cells exhibit hallmarks of functional immaturity. In this Opinion, we focus on reactive oxygen species (ROS), signaling molecules that can potentially modulate cardiac maturation. We outline how ROS impacts nearly every aspect associated with cardiac maturation, including contractility, calcium handling, metabolism, and hypertrophy. Though the precise role of ROS in cardiac maturation has yet to be elucidated, ROS may provide a valuable perspective for understanding the molecular mechanisms for cardiac maturation under various conditions.


Cody Publishes in JoVE

We are excited to announce that a detailed protocol of our work recently published in Tissue Engineering, Part A, has been accepted for publication in the Journal of Visualized Experiments (JoVE). Congratulations Cody! The publication is linked here and the abstract can be found below:

Endothelial progenitors derived from induced pluripotent stem cells (iPSC-EPs) have the potential to revolutionize cardiovascular disease treatments and to enable the creation of more faithful cardiovascular disease models. Herein, the encapsulation of iPSC-EPs in three-dimensional (3D) collagen microenvironments and a quantitative analysis of these cells’ vasculogenic potential are described.


Alicia Publishes in Tissue Engineering, Part A

Congratulations to our recent Ph.D. graduate, Dr. Alicia Allen, whose work was published in Tissue Engineering, Part A! The paper, titled “Temporal Impact of Substrate Anisotropy on Differentiating Cardiomyocyte Alignment and Functionality”, examines how differential fiber alignment on electrospun scaffolds affects the differentiation and final function of mESC-derived cardiomyocytes. The paper can be found here and the abstract is listed below:

Anisotropic biomaterials can affect cell function by driving cell alignment, which is critical for cardiac engineered tissues. Recent work, however, has shown that pluripotent stem cell-derived cardiomyocytes may self-align over long periods of time. To determine how the degree of biomaterial substrate anisotropy impacts differentiating cardiomyocyte structure and function, we differentiated mESCs to cardiomyocytes on non-aligned, semi-aligned, and aligned fibrous substrates and evaluated cell alignment, contractile displacement, and calcium transient synchronicity over time. Although cardiomyocyte gene expression was not affected by fiber alignment, we observed gradient- and threshold-based differences in cardiomyocyte alignment and function. Cardiomyocyte alignment increased with the degree of fiber alignment in a gradient-based manner at early time points and in a threshold-based manner at later time points. Calcium transient synchronization tightly followed cardiomyocyte alignment behavior, allowing highly anisotropic biomaterials to drive calcium transient synchronization within 8 days, while such synchronized cardiomyocyte behavior required 20 days of culture on non-aligned biomaterials. In contrast, cardiomyocyte contractile displacement had no directional preference on day 8 yet became anisotropic in the direction of fiber alignment on aligned fibers by day 20. Biomaterial anisotropy impact on differentiating cardiomyocyte structure and function is temporally-dependent.


Cody Publishes in Regenerative Biomaterials

We recently published our review by Crosby and Zoldan titled, “Mimicking the physical cues of the ECM in angiogenic biomaterials”, in the journal Regenerative Biomaterials. Thank you to chief editor and UT professor Dr. Nicholas Peppas for the opportunity to publish our summary and predictions for this burgeoning field! The abstract is listed below and the paper can be accessed here:

A functional microvascular system is imperative to build and maintain healthy tissue. Impaired microvasculature results in ischemia, thereby limiting the tissue’s intrinsic regeneration capacity. Therefore, the ability to regenerate microvascular networks is key to the development of effective cardiovascular therapies. To stimulate the formation of new microvasculature, researchers have focused on fabricating materials that mimic the angiogenic properties of the native extracellular matrix (ECM). Here, we will review biomaterials that seek to imitate the physical cues that are natively provided by the ECM to encourage the formation of microvasculature in engineered constructs and ischemic tissue in the body.

Cody Publishes in Tissue Engineering, Part A

Congratulations to Cody Crosby whose publication, “Quantifying the vasculogenic potential of iPSC-derived EPs in collagen hydrogels”, was accepted and is now available online in Tissue Engineering, Part A! The abstract can be found below:

Induced pluripotent stem cell-derived endothelial progenitors (iPSC-EPs) have emerged as a promising candidate cell source for patient-specific ischemic therapies. Before these cells can be appropriately deployed in a clinical setting, it is imperative to study their assembly into functional vascular networks in extracellular matrix (ECM)-mimicking, three-dimensional microenvironments. To elucidate the interactions of iPSC-EPs with the ECM, we examined how in vitro modulation of structural protein density, the presence of angiogenic growth factors, and relative proteolytic activity affected the vasculogenic potential of these progenitors, i.e., their ability to self-assemble into vessel-like networks. We found that the addition of a ROCK pathway inhibitor and exogenous vascular endothelial growth factor (VEGF) are imperative for inducing robust iPSC-EP vasculogenesis in collagen hydrogels. Under these conditions, 3D vascular-like networks containing VE-cadherin-expressing lumens formed within a week of culture. To quantify this 3D vessel-like network, we developed a computational pipeline to analyze network length, connectivity, and average lumen diameter. Increasing the concentration of collagen in the hydrogels abrogated network formation and encouraged the formation of disconnected, large-diameter lumens. This phenomenon was in part related to the cells’ proteolytic capacity and the hydrogels’ properties, specifically hydrogel deformability and pore size. In conclusion, we demonstrate that the vasculogenic potential of iPSC-EPs is regulated by cell-matrix interactions and the matrix properties of collagen hydrogels.

Chengyi Publishes in Experimental Cell Research

Congratulations to Chengyi Tu, whose publication, “Commonly used thiol-containing antioxidants reduce cardiac differentiation and alter gene expression ratios of sarcomeric isoforms”, was recently accepted and is now published in Experimental Cell Research! The abstract can be found below:

Reactive oxygen species (ROS) scavengers such as beta-mercaptoethanol (BME) and monothiol glycerol (MTG) are extensively used in stem cell research to prevent cellular oxidative stress. However, how these antioxidant supplements impact stem cell cardiac differentiation, a process regulated by redox-signaling remains unknown. In this study, we found that removal of BME from the conventional high-glucose, serum-based differentiation medium improved cardiac differentiation efficiency by 2-3 fold. BME and MTG treatments during differentiation significantly reduced mRNA expression of cardiac progenitor markers (NKX2.5 and ISL1) as well as sarcomeric markers (MLC2A, MLC2V, TNNI3, MYH6 and MYH7), suggesting reduced cardiomyogenesis by BME or MTG. Moreover, BME and MTG altered the expression ratios between the sarcomeric isoforms. In particular, TNNI3 to TNNI1 ratio and MLC2V to MLC2A ratio were significantly lower in BME or MTG treated cells than untreated cells, implying altered cardiomyocyte phenotype and maturity. Lastly, BME and MTG treatments resulted in less frequent beating, slower contraction and relaxation velocities than untreated cells. Interestingly, none of the above-mentioned effects was observed with Trolox, a non-thiol based antioxidant, despite its strong antioxidant activity. This work demonstrates that commonly used antioxidant supplements may cause considerable changes to cellular redox state and the outcome of differentiation.

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