Gordana Vunjak-Novakovic

Columbia University | CU · Biomedical Engineering Ph.D. Program

Ionizable lipid nanoparticles (LNPs) have been pivotal in combating COVID-19, and numerous preclinical and clinical studies have highlighted their potential in nucleic acid-based therapies and vaccines. However, the effectiveness of endosomal escape for the nucleic acid cargos encapsulated in LNPs is still low, leading to suboptimal treatment outco...

Epicardial cells (EPIs) form the outer layer of the heart and play an important role in development and disease. Current heart‐on‐a‐chip platforms still do not fully mimic the native cardiac environment due to the absence of relevant cell types, such as EPIs. Here, using the Biowire II platform, engineered cardiac tissues with an epicardial outer l...

italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">Goal: Contractile response and calcium handling are central to understanding cardiac function and physiology, yet existing methods of analysis to quantify these metrics are often time-consuming, prone to mistakes, or require specialized equipment/licen...

Prostate cancer is the most common cancer in men and the second-leading cause of death. Most prostate cancer deaths are due to metastasis, particularly to the bone. Metastasis occurs when cells from the primary tumor travel through the blood as circulating tumor cells (CTCs) and settle in metastatic sites. CTCs are difficult to collect from patient...

Systemic lupus erythematosus (SLE) is a highly heterogenous autoimmune disease that affects multiple organs, including the heart. The mechanisms by which myocardial injury develops in SLE, however, remain poorly understood. Here we engineered human cardiac tissues and cultured them with IgG fractions containing autoantibodies from SLE patients with...

Most cancer deaths are due to metastatic dissemination to distant organs. Bone is the most frequently affected organ in metastatic prostate cancer and a major cause of prostate cancer deaths. Yet, our partial understanding of the molecular factors that drive bone metastasis has been a limiting factor for developing preventative and therapeutic stra...

Pulmonary air leak is the most common complication of lung surgery, contributing to post‐operative morbidity in up to 60% of patients; yet, there is no reliable treatment. Available surgical sealants do not match the demanding deformation mechanics of lung tissue; and therefore, fail to seal air leak. To address this therapeutic gap, a sealant with...

Vascular malformation, a key clinical phenotype of Proteus syndrome, lacks effective models for pathophysiological study and drug development due to limited patient sample access. To bridge this gap, we built a human vascular organoid model replicating Proteus syndrome's vasculature. Using CRISPR/Cas9 genome editing and gene overexpression, we crea...

Objective: Robot-assisted minimally invasive surgery remains limited by the absence of haptic feedback, which surgeons routinely rely on to assess tissue stiffness. This limitation hinders surgeons' ability to identify and treat abnormal tissues, such as tumors, during robotic surgery. Methods: To address this challenge, we developed a robotic t...

Although lung disease is a major cause of mortality, the mechanisms involved in human lung regeneration are unclear because of the lack of experimental models. Here we report a novel model where human pluripotent stem cell-derived expandable cell lines sharing features of airway secretory and basal cells engraft in the distal rat lung after conditi...

Hematopoietic stem cells (HSCs) regenerate after myeloablation, a procedure that adversely disrupts the bone marrow and drives leptin receptor-expressing cells, a key niche component, to differentiate extensively into adipocytes. Regeneration of the bone marrow niche is associated with the resolution of adipocytes, but the mechanisms remain poorly...

BAG3 levels are diminished in patients with heart failure and several mutations have been identified to cause dilated cardiomyopathy with cardiac fibrosis. BAG3’s four binding domains are critical to its function to facilitate proteostasis. BAG3’s role has been extensively studied in CMs, where it aids sarcomere protein turnover through chaperone-a...

A considerable number of patients with systemic lupus erythematosus (SLE) develop myocardial injury. SLE patients have highly heterogenous populations of autoantibodies that may contribute to cardiac disease pathogenesis and heterogeneity; however, little is known about their direct role in myocardial injury. Here, we engineered a model of matured...

In the native human myocardium, cardiac resident macrophages are a critical mediator for normal cardiac function, performing a variety of biological roles in electrical conduction, regeneration, and phagocytosis and efferocytosis. However, most models of human engineered cardiac tissues (hECT), which aim to recapitulate the native adult myocardium...

Cosmic radiation is the most serious risk that will be encountered during the planned missions to the Moon and Mars. There is a compelling need to understand the effects, safety thresholds, and mechanisms of radiation damage in human tissues, in order to develop measures for radiation protection during extended space travel. As animal models fail t...

My laboratory has a longstanding interest in developing mouse models of prostate cancer that recapitulate the broad spectrum of prostate cancer phenotypes. We have been employing state-of-the-art systems biology approaches to integrate molecular data from our mouse models with comparable data from human prostate cancer, with the ultimate goal of in...

Background: Severe Coronavirus Disease 2019 (COVID-19) infection is associated with prolonged intubation and its complications. Tracheal stenosis is one such complication that may require specialized surgical management. We aimed to describe the surgical management of post-COVID-19 tracheal stenosis. Methods: This case series describes consecuti...

In tissue development and homeostasis, transforming growth factor (TGF)-β signaling is finely coordinated by latent forms and matrix sequestration. Optogenetics can offer precise and dynamic control of cell signaling. We report the development of an optogenetic human induced pluripotent stem cell system for TGF-β signaling and demonstrate its utili...

The airway epithelium lining the luminal surface of the respiratory tract creates a protective barrier that ensures maintenance of tissue homeostasis and prevention of respiratory diseases. The airway epithelium, unfortunately, is frequently injured by inhaled toxic materials, trauma, or medical procedures. Substantial or repeated airway epithelial...

Valvular heart disease is a globally prevalent cause of morbidity and mortality, with both congenital and acquired clinical presentations. Tissue engineered heart valves (TEHVs) have the potential to radically shift the treatment landscape for valvular disease by functioning as life-long valve replacements that overcome the current limitations of b...

Restrictive cardiomyopathy (RCM) is defined as increased myocardial stiffness and impaired diastolic relaxation leading to elevated ventricular filling pressures. Human variants in filamin C (FLNC) are linked to a variety of cardiomyopathies, and in this study, we investigate an in-frame deletion (c.7416_7418delGAA, p.Glu2472_Asn2473delinAsp) in a...

Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular and interorgan communication. The capability to modulate their stability, tissue-specific targeting and cargo render EVs as promising nanotherapeutics for treating heart, lung, blood an...

Heart failure (HF) is characterized by global alterations in myocardial DNA methylation, yet little is known about epigenetic regulation of the non-coding genome and potential reversibility of DNA methylation with left ventricular assist device (LVAD) therapy. Genome-wide mapping of myocardial DNA methylation in 36 HF patients at LVAD implantation,...

The severe shortage of functional donor lungs that can be offered to recipients has been a major challenge in lung transplantation. Innovative ex vivo lung perfusion (EVLP) and tissue engineering methodologies are now being developed to repair damaged donor lungs that are deemed unsuitable for transplantation. To assess the efficacy of donor lung r...

Researchers are exploring sex differences in experimental models of both development and disease-but are we doing enough? In this collection of Voices, we celebrate researchers who are asking this question and starting to offer mechanistic clues on sexually dimorphic differences seen in interorgan communication, metabolic disease, neurological diso...

Introduction: Dysregulation of cardiac kinases occurs in cardiovascular diseases including hypertrophy, remodeling and ischemia injury. Serine/threonine protein kinase 25 (STK25) is a stress response kinase and putative tumor suppressor that regulates cell survival and metabolism through several signaling pathways, including LATS/3HIPPO and mTOR pa...

Background Xenogeneic cross-circulation (XC) is an experimental method for ex vivo organ support and recovery that could expand the pool of donor lungs suitable for transplantation. The objective of this study was to establish and validate a standardized, reproducible, and broadly applicable technique for performing xenogeneic XC to support and rec...

Acute leukemias represent the most frequent type of cancer (∼30%) in children and young adults. The lack of robust systems for in vitro culture of primary leukemia samples is a significant barrier for the development of effective genetic and chemical screens for novel therapeutic targets in pediatric leukemia. In vitro systems, including engineered...

Bone grafts can be engineered by differentiating human mesenchymal stromal cells (MSCs) via the endochondral and intramembranous ossification pathways. We evaluated the effects of each pathway on the properties of engineered bone grafts and their capacity to drive bone regeneration. Bone-marrow-derived MSCs were differentiated on silk scaffolds int...

Engineered cardiac tissues derived from human induced pluripotent stem cells offer unique opportunities for patient-specific disease modeling, drug discovery and cardiac repair. Since the first engineered hearts were introduced over two decades ago, human induced pluripotent stem cell-based three-dimensional cardiac organoids and heart-on-a-chip sy...

Despite over thirty years of intensive research for targeted therapies, treatment of Acute Respiratory Distress Syndrome (ARDS) remains supportive in nature. With mortality upwards of 30%, a high-fidelity pre-clinical model of ARDS on which to test novel therapeutics is critically needed. We aimed to induce a reproducible model of ARDS in human-siz...

Introduction: Mutations in BAG3 result in dilated cardiomyopathy with cardiac fibrosis. Currently, the role of BAG3 in non-myocyte cell types is not known. We tested the hypothesis that BAG3 controls cardiac fibroblast (CF) function and that the loss of fibroblast-specific BAG3 is deleterious, using cells and engineered cardiac tissues (ECT) derive...

Future lunar missions and beyond will require new and innovative approaches to radiation countermeasures. The Translational Research Institute for Space Health (TRISH) is focused on identifying and supporting unique approaches to reduce risks to human health and performance on future missions beyond low Earth orbit. This paper will describe three f...

In the heart, protein kinase A (PKA) is critical for activating calcium handling and sarcomeric proteins in response to beta-adrenergic stimulation leading to increased myocardial contractility and performance. The catalytic activity of PKA is tightly regulated by regulatory subunits that inhibit the catalytic subunit until released by cAMP binding...

Pulmonary air leak is the most common complication of lung surgery, with air leaks that persist longer than 5 days representing a major source of post‐surgery morbidity. Clinical management of air leaks is challenging due to limited methods to precisely locate and assess leaks. Here, we present a sound‐guided methodology that enables rapid quantita...

Background Manifestations of cystic fibrosis, although well-characterized in the proximal airways, are understudied in the distal lung. Characterization of the cystic fibrosis lung ‘matrisome’ (matrix proteome) has not been previously described, and could help identify biomarkers and inform therapeutic strategies. Methods We performed liquid chrom...

Organs-on-chips (OoCs) are systems containing engineered or natural miniature tissues grown inside microfluidic chips. To better mimic human physiology, the chips are designed to control cell microenvironments and maintain tissue-specific functions. Combining advances in tissue engineering and microfabrication, OoCs have gained interest as a next-g...

Many neuromuscular diseases, such as myasthenia gravis (MG), are associated with dysfunction of the neuromuscular junction (NMJ), which is difficult to characterize in animal models due to physiological differences between animals and humans. Tissue engineering offers opportunities to provide in vitro models of functional human NMJs that can be use...

Repeated injury to airway tissue can impair lung function and cause chronic lung disease, such as chronic obstructive pulmonary disease. Advances in regenerative medicine and bioreactor technologies offer opportunities to produce lab-grown functional tissue and organ constructs that can be used to screen drugs, model disease, and engineer tissue re...

Advances in self-organizing cardiac organoids to recapitulate human cardiogenesis have provided a powerful tool for unveiling human cardiac development, studying cardiovascular diseases, testing drugs, and transplantation. Here, we highlight the recent remarkable progress on multicellular cardiac organoids and review the current status for their pr...

Engineered tissues can be used to model human pathophysiology and test the efficacy and safety of drugs. Yet, to model whole-body physiology and systemic diseases, engineered tissues with preserved phenotypes need to physiologically communicate. Here we report the development and applicability of a tissue-chip system in which matured human heart, l...

Engineered human cardiac tissues facilitate progress in regenerative medicine, disease modelling and drug development. In this Perspective, we reflect on the most notable advances in cardiac tissue engineering from the past two decades by analysing pivotal studies and critically examining the most consequential developments. This retrospective anal...

Purpose: Gradual elevation of periosteum from the bone surface is known to promote the adaptation of soft tissues and the formation of hard tissues. The aim of our study was to estimate the benefit of periosteal distraction osteogenesis (PDO) on de novo bone formation in a rat model. Materials and methods: After device placement, animals were al...

Background Human heart failure is characterized by global alterations in the myocardial DNA methylation profile, yet little is known about epigenetic regulation of non-coding transcripts and potential reversibility of DNA methylation with left ventricular assist device (LVAD) support. Method Genome-wide mapping of myocardial DNA methylation was pe...

Major progress in the understanding and treatment of cancer have tremendously improved our knowledge of this complex disease and improved the length and quality of patients’ lives. Still, major challenges remain, in particular with respect to cancer metastasis which still escapes effective treatment and remains responsible for 90% of cancer related...

Recent synergistic advances in organ-on-chip and tissue engineering technologies offer opportunities to create in vitro-grown tissue or organ constructs that can faithfully recapitulate their in vivo counterparts. Such in vitro tissue or organ constructs can be utilized in multiple applications, including rapid drug screening, high-fidelity disease...

Ischemic and non-ischemic cardiomyopathies have distinct etiologies and underlying disease mechanisms, which require in-depth investigation for improved therapeutic interventions. The goal of this study was to use clinically obtained myocardium from healthy and heart failure patients, and characterize the changes in extracellular matrix (ECM) in is...

Osteoarthritis (OA) is the most common joint disease worldwide, yet we continue to lack an understanding of disease etiology and pathology, and effective treatment options. Essential to tissue homeostasis, disease pathogenesis, and therapeutic responses are the stratified organization of cartilage and the crosstalk at the osteochondral junction. An...

In the heart, Protein Kinase A (PKA) is critical for activating calcium handling and sarcomeric proteins in response to beta adrenergic stimulation leading to increased myocardial contractility and performance. The catalytic activity of PKA is tightly regulated by regulatory subunits which inhibit the catalytic subunit until released by cAMP bindin...

Injured or diseased airway epithelium due to repeated environmental insults or genetic mutations can lead to a functional decline of the lung and incurable lung diseases. Bioengineered airway tissue constructs can facilitate in vitro investigation of human lung diseases and accelerate the development of effective therapeutics. Here, we report robus...

Recent synergistic advances in organ-on-chip and tissue engineering technologies offer opportunities to create in vitro- grown tissue or organ constructs that can faithfully recapitulate their in vivo counterparts. Such in vitro tissue or organ constructs can be utilized in multiple applications, including rapid drug screening, high-fidelity diseas...

Hypothesis: STK25 regulates cell survival, metabolism and cardiac function through phosphorylating PKA R1α and modulating PKA signaling pathway in human cardiomyocytes. Background: Dysregulation of cardiac kinases are related with many cardiovascular diseases including hypertrophy, remodeling and ischemia injury. STK25 is a stress response kinase t...

Extracellular vesicles (EVs) are carriers of biological signals through export and delivery of RNAs and proteins. Of increasing interest is the use of EVs as a platform for delivery of biomolecules. Preclinical studies have effectively used EVs to treat a number of diseases. Uniquely, endogenous machinery within cells can be manipulated in order to...

Engineered Vascularized Flaps In article number 2008687, Shulamit Levenberg and co‐workers fabricate composite neo‐tissue flaps by combining polymeric matrices and decellularized bone. These are perfused in vivo using hosts via a potent neo‐vascular network. In vivo imaging is utilized to show how composite flaps support long‐term bone repair and v...

The convergence of tissue engineering and patient-specific stem cell biology has enabled the engineering of in vitro tissue models that allow the study of patient-tailored treatment modalities. However, sex-related disparities in health and disease, from systemic hormonal influences to cellular-level differences, are often overlooked in stem cell b...

We explore the utility of bioengineered human tissues-individually or connected into physiological units-for biological research. While much smaller and simpler than their native counterparts, these tissues are complex enough to approximate distinct tissue phenotypes: molecular, structural, and functional. Unlike organoids, which form spontaneously...

Purpose of Review Adult human hematopoiesis resides in the bone marrow (BM), which is comprised of multiple niches capable of supporting hematopoietic stem and progenitor cells (HSPCs), as well as their downstream lineages. In maintaining the blood-forming cells of the body, the BM microenvironment is spatially regulated by a number of stromal supp...

Although machine perfusion has gained momentum as an organ preservation technique in liver transplantation, persistent organ shortages and high waitlist mortality highlight unmet needs for improved organ salvage strategies. Beyond preservation, extracorporeal organ support platforms can also aid the development and evaluation of novel therapeutics....

For decades, fetal bovine serum (FBS) has been used routinely for culturing many cell types, based on its empirically demonstrated effects on cell growth, and the lack of suitable non-xenogeneic alternatives. The FBS-based culture media do not represent the human physiological conditions, and can compromise biomimicry of preclinical models. To reca...

Neuroblastoma (NB) is the most common extracranial pediatric solid cancer originating from undifferentiated neural crest cells. NB cells express EZH2 and GLI1 genes that are known to maintain the undifferentiated phenotype of cancer stem cells (CSC) in NB. Recent studies suggest that tumor-derived extracellular vesicles (EVs) can regulate the trans...

Functional human tissues engineered from patient-specific induced pluripotent stem cells (hiPSCs) hold great promise for investigating the progression, mechanisms, and treatment of musculoskeletal diseases in a controlled and systematic manner. For example, bioengineered models of innervated human skeletal muscle could be used to identify novel the...

Tissue engineering has markedly matured since its early beginnings in the 1980s. In addition to the original goal to regenerate damaged organs, the field has started to explore modeling of human physiology “in a dish.” Induced pluripotent stem cell (iPSC) technologies now enable studies of organ regeneration and disease modeling in a patient-specif...

In living tissues, mechanical stiffness and biological function are intrinsically linked. Alterations in the stiffness of tissues can induce pathological interactions that affect cellular activity and tissue function. Underlying connections between tissue stiffness and disease highlights the importance of accurate quantitative characterizations of...

Recent engineering technologies have transformed traditional perspectives of cancer to include the important role of the extracellular matrix (ECM) in recapitulating the malignant behaviors of cancer cells. Novel biomaterials and imaging technologies have advanced our understanding of the role of ECM density, structure, mechanics and remodeling in...

Fibrosis of the knee is a common disorder resulting from an aberrant wound healing response and is characterized by extracellular matrix deposition, joint contraction, and scar tissue formation. The principal regulator of the fibrotic cascade is transforming growth factor beta-1 (TGF-β1), a factor that induces rapid proliferation and differentiatio...

Functional regeneration of complex large‐scaled defects requires both soft‐ and hard‐tissue grafts. Moreover, bone constructs within these grafts require an extensive vascular supply for survival and metabolism during the engraftment. Soft‐tissue pedicles are often used to vascularize bony constructs. However, extensive autologous tissue‐harvest re...

Current interventions fail to recover injured myocardium after infarction and prompt the need for development of cardioprotective strategies. Of increasing interest is the therapeutic use of microRNAs to control gene expression through specific targeting of mRNAs. In this Review, we discuss current microRNA-based therapeutic strategies, describing...

Most cancer deaths are due to tumor metastasis rather than the primary tumor. Metastasis is a highly complex and dynamic process that requires orchestration of signaling between the tumor, its local environment, distant tissue sites, and immune system. Animal models of cancer metastasis provide the necessary systemic environment, but lack control o...

Gastrointestinal disease burden continues to rise in the United States and worldwide. The development of bioengineering strategies to model gut injury or disease and to reestablish functional gut tissue could expand therapeutic options and improve clinical outcomes. Current approaches leverage a rapidly evolving gut bioengineering toolkit aimed at...

Extracellular matrix is known to regulate vascularization by a sequence of multiple factors including mechanical forces. In this issue of Cell Stem Cell, Wei et al. (2020) investigate the roles of matrix biomechanics on early stages of vasculogenesis by using hydrogels with tunable stiffness and stress relaxation.

Traditional in-vitro models of solid bone tumors used in basic and preclinical research are unable to faithfully recapitulate human physiology. Specifically, monolayer cultures of osteosarcoma fail to recapitulate various features of 3D tumors, and they lack the native bone milieu, where tumor growth, metastasis, and response to therapy are critica...

Joint disorders can be detrimental to quality of life. There is an unmet need for precise functional reconstruction of native-like cartilage and bone tissues in the craniofacial space and particularly for the temporomandibular joint (TMJ). Current surgical methods suffer from lack of precision and comorbidities and frequently involve multiple opera...

Traditional drug screening models are often unable to faithfully recapitulate human physiology in health and disease, motivating the development of microfluidic organs-on-a-chip (OOC) platforms that can mimic many aspects of human physiology and in the process alleviate many of the discrepancies between preclinical studies and clinical trials outco...

Strategies to regenerate cardiac tissue postinjury are limited and heart transplantation remains the only 'cure' for a failing heart. Extracellular vesicles (EVs), membrane-bound cell secretions important in intercellular signaling, have been shown to play a crucial role in regulating heart function. A mechanistic understanding of the role of EVs i...

In article number 1910811, Gordana Vunjak‐Novakovic, Sharon Fleischer, and Daniel Naveed Tavakol review approaches to engineering the human vascular tree, ranging from millimeter‐sized arteries to micro‐scaled capillaries. Strategies for engineering vascularized tissues, challenges limiting their translation into clinic, and perspectives on future...

Patients awaiting lung transplantation face high wait-list mortality, as injury precludes the use of most donor lungs. Although ex vivo lung perfusion (EVLP) is able to recover marginal quality donor lungs, extension of normothermic support beyond 6 h has been challenging. Here we demonstrate that acutely injured human lungs declined for transplant...

From microscaled capillaries to millimeter‐sized vessels, human vasculature spans multiple scales and cell types. The convergence of bioengineering, materials science, and stem cell biology has enabled tissue engineers to recreate the structure and function of different hierarchical levels of the vascular tree. Engineering large‐scale vessels aims...

The shortage of transplantable donor organs directly affects patients with end-stage lung disease, for which transplantation remains the only definitive treatment. With the current acceptance rate of donor lungs of only 20%, rescuing even one half of the rejected donor lungs would increase the number of transplantable lungs threefold, to 60%. We re...

In this short review, we draw parallels and stress differences between heart regeneration in mice and human, from a bioengineering perspective. As the prevailing dogma that the adult heart is completely post-mitotic is starting to change, there are multiple opportunities for augmenting the limited but definitive turnover of cardiomyocytes, to the e...

The respiratory system, which includes the trachea, airways, and distal alveoli, is a complex multi-cellular organ that intimately links with the cardiovascular system to accomplish gas exchange. In this review and as members of the NIH/NHLBI-supported Progenitor Cell Translational Consortium, we discuss key aspects of lung repair and regeneration....

Articular cartilage injuries are a common source of joint pain and dysfunction. We hypothesized that pulsed electromagnetic fields (PEMFs) would improve growth and healing of tissue‐engineered cartilage grafts in a direction‐dependent manner. PEMF stimulation of engineered cartilage constructs was first evaluated in vitro using passaged adult canin...

In the developed world, cardiovascular disease is responsible for the loss of more human lives than all cancer combined. Due to the minimal intrinsic ability of adult heart to regenerate itself following injury, the myocardial infarction results in rapid death of hundreds of millions of cardiomyocytes (CMs), and vigorous inflammatory response. Over...