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Ke Cheng

Bio

Ke is Professor in the Department of Molecular Biomedical Sciences at the College of Veterinary Medicine and Professor in the UNC/NCSU joint Department of Biomedical Engineering. He is also an adjunct professor at the UNC Eshelman School of Pharmacy and UNC School of Medicine. He directs the BioTherapeutics Lab which focuses on stem cells, biomaterials, and nanomedicine for heart and lung regeneration. His lab also studies novel mechanisms of cell extravasation, termed angiopellosis.

Prior to this position, Ke was an Assistant Professor at Cedars-Sinai Medical Center and University of California Los Angeles School of Medicine, where his research focused on stem cells and regenerative medicine in animal models. Ke also served as the director of the stem cell lab for multiple clinical trials including a clinical trial using patient’s own cardiac stem cells to treat heart attack. Ke’s formal education began with a B.S. in Pharmaceutical Engineering from the Zhejiang University, followed by a Ph.D. degree in Biological Engineering from University of Georgia.

AFFILIATIONS

NCSU Faculty Cluster: Translational Regenerative Medicine
American Heart Association
Biomedical Engineering Society

Area(s) of Expertise

REGENERATIVE MEDICINE, VETERINARY CANCER CARE
Dr. Ke Cheng’s laboratory studies regenerative medicine by using patient-derived stem cells, biomaterials, exosomes, micro-RNAs and bioengineering approaches. Translational research is a major focus of the lab. Prior to the launch of Cheng Lab at North Carolina, Dr. Cheng directed a stem cell lab for multiple human trials, including the world’s first clinical trial using cardiac stem cells to treat heart attack. Currently, we are interested in isolating patient-specific and organ-specific adult stem cells and testing their regenerative potential in small/large animal models of diseases. Another focus of the lab is to identify novel micro-RNAs involved in tissue protection and regeneration. The lab is also interested in understanding the mechanisms of stem cell migration and extravasation after delivery. Dr. Cheng also holds an Full Professor appointment at the UNC/NCSU Joint Department of Biomedical Engineering, where his research focuses on the development of novel nano theranostic agents for regenerative medicine as well as bioengineering approaches to augment stem cell engraftment and potency.

Publications

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Grants

Date: 09/20/21 - 9/30/24
Amount: $6,277,542.00
Funding Agencies: National Institutes of Health (NIH)

The overall goal of this project is to design, construct and outfit a swine biomedical research facility on the campus of the fourth ranked College of Veterinary Medicine in the United States with ready access to trained veterinary specialists and state of the art biomedical (e.g. MRI, CT and nuclear medicine) facilities. The facility will provide additional high-quality space for biomedical research by NIH funded faculty from NC State University, Duke University and the University of North Carolina. The design and construction of the swine biomedical research facility will feature a free-standing masonry and steel building that will house the production and care of gnotobiotic and gene-edited swine, as well as state-of-the-art procedures (surgical, telemetry, arthroscopy, endoscopy). In addition, the unit includes flexible space that can accommodate pregnant and non-pregnant sows, and farrowing facilities to generate needed gene edited progeny from our own lines as well as those obtained from the NIH-supported NSRRC. Procedural space will provide a sterile surgery suite (two tables) to accommodate an increasing bioengineering need for endoscopic and arthroscopic procedures. The building will be placed immediately adjacent to space (referred to as the G20 facility) previously created for the use of severe combined immunodeficiency and other gene edited miniature or juvenile pigs (G20 OD020279) to allow for shared use of the space when possible. The proposed facility has been designed to maximize synergy and minimize overlap with the G20 space. Combined they will give us a high degree of flexibility and will allow us to conduct a broad range of research thus having a broad impact across multiple NIH Centers/Institutes. This project team is uniquely situated to drive the design and development of this facility and the expansion of this program. By serving in leadership roles within the College of Veterinary Medicine and NC State University we have the ability to provide access to the veterinary college biomedical campus, the research animal facilities and the state-of-the-art equipment in the tertiary care veterinary hospital. Our team of investigators has comparative medicine expertise and an extensive collaborative network with biomedical researchers at Duke and the University of North Carolina. As a team, we have successfully managed infrastructure grants, such as the expansion of facilities for housing and studying transgenic and non-transgenic miniature pigs (G20 OD020279) and building projects including a 20,000 square foot wet lab and GMP lab space.

Date: 07/01/21 - 6/30/24
Amount: $230,908.00
Funding Agencies: American Heart Association

unctions. Stem cell therapy represents a promising strategy in regenerative medicine. Emerging lines of evidence indicate that stem cells exert their beneficial effects mainly through secretion of regenerative factors2. However, live cells need to be carefully preserved and processed before usage. In addition, cell transplantation carries certain immunogenicity and/or tumorigenicity risks3. The development of cell-free and non-living therapeutics derived from stem cells has the potential to revolutionize current regenerative medicine practice. To those ends, our lab has fabricated cell-mimicking synthetic cardiac stromal cells (synCSC) that comprises a biodegradable polymer particle containing cell-secreted factors as the core and cell mimicking membranes on the shell (Tang et al. Nature Comms 20174). We started with Poly Lactic-co-Glycolic Acid (PLGA) as the building material. As a biocompatible and biodegradable polymer, PLGA has provided a safe and non-toxic building block for various control-release systems. To enhance the delivery efficiency of synCSCs, my PhD work lead to the development an off-the-shelf cardiac patch (artCP) (Huang et al. Sci. Transl. Med. 20205) by embedding optimized synCSCs into decellularized myocardium extracellular matrix (myoECM). This study extended from the previous mouse acute MI model to rat acute and pig acute MI models and showed impressive cryo-stability, biocompatibility, and therapeutic efficacy.

Date: 04/01/19 - 3/31/24
Amount: $400,000.00
Funding Agencies: American Heart Association

Cardiovascular disease remains as the No. 1 killer in western societies. Currently, ischemic damage to the heart cannot be repaired by conventional medical care therefore only palliative treatments exist. Preclinical animal data and recently completed clinical trials have indicated that transplantation of adult stem cells such as cardiospherederived cells (CDCs) is a promising strategy for therapeutic cardiac regeneration. However, live cells must be carefully preserved to keep them alive and functioning until the time of transplant, and there are some risks involved in cell transplantation. The development of cell-free and non-living therapeutics (e.g. proteins, nucleic acids) derived from stem cells has the potential to revolutionize cardiovascular regenerative medicine. Mounting lines of evidence suggest that therapeutic stem cells (including CDCs) secrete paracrine factors that promote endogenous heart repair. Among those secreted substances, exosomes (EXOs) are secreted by a wide range of cell types including CDCs. We have shown that CDC EXOs are enriched with microRNAs (miRs) and they promote cardiac regeneration in mice with myocardial infraction (MI). AIM 1: Fabricate artEXOs (containing miR-146a, miR-22, miR- 24, and miR-210) and determine their therapeutic benefits in a mouse model of acute MI. AIM 2: Unveil the molecular basis underlying the therapeutic benefits of artEXOs in the post-MI heart. AIM 3: Develop MI-targeted artEXOs for treating acute MI.

Date: 09/01/12 - 8/31/23
Amount: $37,836,660.00
Funding Agencies: National Science Foundation (NSF)

Advanced Self-powered Systems of Integrated Sensor Technologies (ASSIST) vision is to be a dynamic leader in development of wearable, self-powered integrated sensor technologies for continuous health and environmental monitoring. These technologies will directly respond to NAE?s Grand Challenge to advance health informatics to improve acquisition, management and use of health information to enhance medical care, correlate disease and environment and revolutionize response to public health emergencies, disasters, pandemics and/or chem-bio attacks. ASSIST?s mission is to transform US and global health informatics, electronics and biomedical engineering industries through development and demonstration of fundamental and enabling nanotechnologies for energy harvesting, battery-free energy storage and ultra-low power computation and communication, integrated with physiological and environmental nanosensors and biocompatible materials, to empower personal environmental health monitoring and emergency response. Goals: 1. Advance discovery in energy harvesting and storage, multifunctional sensors and materials, and low-power systems design; 2. Develop enabling technologies for energy conversion, device reliability and ultra-low power computation and communications, with integration to achieve two 1st-generation test-beds: self-sustaining wireless nodes and conformal multifunctional applications; 3. Develop systems integration requirements and demonstrate ?Exposure Track? and ?Emergency Track? testbeds; 4. Develop efficient and secure methods to handle large quantities of data and retrieve patterns of environmental and health correlations; 5. Create a culture of team-based research, education and innovation, cultivating a diverse group of talented, well prepared graduates excited about research, design and production of health informatics and biomedical engineering solutions to improve global health and safety; 6. Form partnerships with precollege institutions to strengthen the STEM pipeline by helping middle and high school students and teachers develop technical literacy and motivation to contribute to solving NAE Grand Challenges; 7. Stimulate entrepreneurship and form sustainable partnerships with small and large firms, health practitioners and emergency responders to link ASSIST discoveries to innovation, accelerated commercialization and job creation. ASSIST integrated sensor technologies will result in a wearable health patch that incorporates energy harvesting and storage, computation and communication, along with low-power integrated sensors for health and environmental exposures. This will be the platform technology that will drive two systems applications related to global health. The first, the Exposure Track, will enable longitudinal, simultaneous monitoring of environmental factors and human health parameters to create an unprecedented set of data to lead to direct understanding of how environment impacts health. This information, of great interest to EPA and CDC, will revolutionize our understanding of environmental health and may impact future regulatory policies. The patch?s self-powered nature will enable critical longitudinal monitoring. This system will involve epidemiologists, social scientists, data mining, pattern recognition professionals and EPA scientists to further understanding of environmental health. The patch will also drive a second system, the Wellness Track, which will aim to empower patients to take charge of their own health by having readily accessible information about their health status. According to the Milken Inst., lifestyle diseases consume 70% of the US?s health care resources and face an unsustainable future in light of rising health care costs. It has been shown that humans are more likely to change lifestyle habits if they witness real-time, positive changes in their health as a result of those changes. The Wellness Track will provide an unobtrusive, battery-free interface for sensing of multiple vital signs, along with advanced and secure communication strateg

Date: 09/01/19 - 7/31/23
Amount: $2,735,616.00
Funding Agencies: National Institutes of Health (NIH)

Stem cell therapy represents a promising strategy in regenerative medicine. However, live cells need to be carefully preserved and processed before usage. In addition, cell transplantation carries certain immunogenicity and/or tumorigenicity risks. The development of cell-free and nonliving therapeutics derived from stem cells has the potential to revolutionize current regenerative medicine practice. Mounting lines of evidences indicate that stem cells exert their beneficial effects mainly through the secretion of pro-regenerative factors. Based on this, we fabricated “synthetic cardiac stem cells (synCSCs)” by encapsulating cardiac stem cell-secreted factors in a biodegradable polymer block. In a mouse model of myocardial infarction (MI), intramyocardial injection of synCSCs led to preservation of viable myocardium and augmentation of cardiac functions similar to real CSC therapy in immunodeficiency mice with myocardial infarction by permanent vessel ligation. Despite the successful proof of concept, a big challenge is the effective delivery of synthetic cells to the heart. The present proposal represents a logic progression from our previous work. Here we will be developing and testing a new entity: an artificial cardiac patch (artCP) formed by embedding synCSCs into decellularized myocardial extracellular matrix (ECM). Our studies will extend from the previous rodent acute MI model to a chronic heart failure model in both small/large animals. The overarching hypothesis is that artCPs can further improve the efficacy of synCSC therapy in rats and pigs with chronic heart injury. Aim 1 is to fabricate artCPs and determine in vitro potency. Aim 2 is to demine the safety and efficacy of artCP therapy in a rat model of chronic infarct. Aim 3 is to translate the findings into a clinically relevant porcine model of advanced cardiomyopathy. Our study will form the foundation for an innovative and “off the shelf” therapy based on stem cell factors and myocardium ECM. The cell-free nature of our approach is more readily translatable to the clinic. Although this particular grant application targets the heart and cardiac stem cells, our approach represents a platform technology that can be applied to the creation of multiple types of synthetic stem cell and ECMs for the repair of various other organs.

Date: 08/15/19 - 7/31/23
Amount: $1,571,573.00
Funding Agencies: National Institutes of Health (NIH)

Arterial and venous thrombosis can cause ischemic injuries in a multitude of tissues. Occlusions can arise slowly from the progression of atherosclerotic disease or acutely due to thrombo-embolization. Serious clinical manifestations of thrombotic occlusions include myocardial infarction (MI), deep vein thrombosis (DVT), and pulmonary embolism (PE). Quickly restoring blood flow is critical for preventing death following thrombotic occlusions, however, reperfusion can result in scar tissue that limits subsequent tissue function. Examples include cardiac fibrosis following MI and post-thrombotic syndrome following DVT. Unfortunately, no effective strategies have been established to prevent fibrosis following thrombos resolution. The objective of this proposal is to develop a novel targeted dual therapeutic system for treatment of thrombotic occlusions that addresses the critical needs to reperfuse the blocked vessel and prevent subsequent fibrosis. We will achieve this by combining a fibrin-targeting particle platform with temporally controlled delivery of a fibrinolytic drug, which will restore blood flow to the ischemic tissue, followed by delivery of a small molecule Rho-associated kinase (ROCK) inhibitor, which will block key cellular responses involved in the onset and progression of fibrosis. This work is significant because it is the first treatment strategy to address the critical needs to quickly reperfuse tissue and subsequent fibrosis following thrombotic occlusions.

Date: 07/01/21 - 6/30/23
Amount: $424,309.00
Funding Agencies: National Institutes of Health (NIH)

As stated in PAR-17-341, the goal of this NIGMS initiative is to .”encourage changes in biomedical graduate training to keep pace with the rapid evolution of the research enterprise that is increasingly complex, interdisciplinary, and collaborative…”. The objective of this Comparative Molecular Medicine Training Program (CMMTP) is to provide a diverse pool of graduate students with rigorous training in biomedical research with special emphasis in team science. Support is requested for three/six students, to be supported by the T32 for a two-year period. The program emphasizes team interdisciplinary research training and provides extensive hands-on experience in challenging research projects focused on comparative molecular medicine, and extensive professional development designed to prepare trainees for a successful career in the biomedical sciences. To achieve our objectives, we have incorporated a set of novel components including: 1) Two Team Science courses, the first led by an Associate Professor with a PhD degree in Communications, focused on developing the communication skills required to successfully participate in team-based collaborative interdisciplinary research, and the second led by the Senior Associate Director for Operations and Academic Programs, Shelton Leadership Center, focused on team leadership skills related to biomedical sciences. 2) A team science mentoring program, the Young Scholar Program (YSP), which provides an opportunity for CMMTP trainees to apply and further refine competencies in project management, mentoring, and effective group communication, including teaching in an undergraduate course in Team Sciences in the Biomedical Sciences. 3) The requirement for the development of a collaborative aim (a coaim) in the trainee’s thesis proposal. 4) A graduate level minor in “Team Leadership and Communication in the Biomedical Sciences". A minor that will help prepare the future leaders in interdisciplinary biomedical research. 5) Close incorporation of science of education expertise within the proposal not only to assess the program, but more importantly, to develop new educational approaches to train PhD students to carry out complex interdisciplinary research in the biomedical sciences. This includes an education/communication PhD student as part of the institutional commitment. This PhD student will use the CMMTP program as the basis for their research on improving education methods in team science. They will ensure that each of our training activities is assessed using evidence-based approaches and that this information is used to further improve methods for team interdisciplinary research training. Other components include: 1) Basing the training grant in the Comparative Medicine Institute (CMI). The CMI’s well established cross-departmental organizational infrastructure facilitates the management and implementation of this training grant, and 2)Extensive professional development activities that include career and academic advising, seminar series, preparation to present orally and in poster format, workshops on scientific communication, among others.

Date: 06/15/22 - 5/31/23
Amount: $370,734.00
Funding Agencies: National Institutes of Health (NIH)

Idiopathic pulmonary fibrosis (IPF) is an ultimately fatal disease whose only curative treatment is lung transplant. IPF is characterized by formation of fibrotic lesions in the lung, eventually resulting in scarring and progressive loss of lung function. Despite some newer treatments, IPF patients still have a median survival rate of only 3-5 years once diagnosed. Clearly, new therapeutic approaches are needed to treat this devastating disease. A promising avenue of approach is stem cell therapy. In the past 8 years, our lab has been developing lung spheroid cells (LSCs) as a novel source of therapeutic lung cells, and FDA approval of clinical trials with LSC treatment of patients with IPF are being pursued. Nonetheless, stem cell-based therapy faces several important limitations. Live cells need to be carefully preserved and processed before usage, and cell transplantation carries certain immunogenicity and tumorigenicity risks. Importantly, live stem cells cannot be delivered to the lung via inhalation, which is the most convenient and effective route to deliver therapeutics to the lung. Recently, we and others have made the novel and exciting observation that many adult stem cells exert their beneficial effects mainly through secretion of regenerative factors that go on to promote endogenous repair. In the preliminary studies that form the basis for this application, we have discovered that secretions from cultured LSCs are just as, if not more, effective than the LSCs themselves in attenuating and resolving IPF in rodent models of the disease. In the quest for active components in the LSC secretions, we found that LSCs secrete large numbers of exosomes (30-150 nm vesicles secreted by numerous cell types). We have shown that exosomes derived from LSCs (LSC-Exo) are therapeutic and regenerative to the injured lung, suggesting these nanostructures are largely responsible for the reparative response to LSC secretions in rodent models of IPF. It is known that exosomes carry microRNAs (miRs) cargoes that could play important roles in cell-cell communication and tissue repair, and indeed we found that LSC-Exo are highly enriched with miR-30a and Let-7. In this proposed study, we plan to determine safety and efficacy as well as medium effective dose of LSC-Exo required for lung repair in rodent models of IPF, to determine the major recipient cells of LSC-Exo in the lung, and determine that the relevant molecular target(s) of exosomal mediated repair and recovery. We hypothesize that key miRs withing LSC-Exo such as miR-30a and Let-7 are mediators of the TGF-beta signaling pathway, using the data produced by scRNA-Seq we will finally determine whether further miR enrichment in these exosomes achieves optimal lung repair. The development of cell-free or non-living therapeutics derived from stem cells has the potential to revolutionize current regenerative medicine practice.

Date: 04/20/20 - 3/31/23
Amount: $2,274,931.00
Funding Agencies: National Institutes of Health (NIH)

Cell-based therapy represents a promising strategy in regenerative medicine. However, live cells need to be carefully preserved and processed before usage. In addition, as “live drugs”, cell transplantation carries certain immunogenicity and/or tumorigenicity risks. The development of cell-free and non-living therapeutics has the potential to revolutionize current regenerative medicine practice. Mounting lines of evidences indicate that adult stem cells exert their beneficial effects mainly through the secretion of pro-regenerative factors. Based on this, the PI Cheng Lab fabricated cell mimicking microparticles (CMMPs) by encapsulating stem cell-secreted factors in a biodegradable polymer block. Our previous studies demonstrated that those “synthetic cells” carried similar secreted proteins and membranes as their parental cells did. In a mouse model of myocardial infarction (MI), intramyocardial injection of CMMPs led to preservation of viable myocardium and augmentation of cardiac functions similar to cell therapy. Despite the successful proof of concept, a big challenge is the effective delivery of those therapeutic microparticles to the heart. Cardiac patches have been tested to deliver therapeutic cells to the surface of the heart. One caveat is that there is a lack of patch-host communication due to poor integration of the cardiac patch with the host myocardium. The MPI Gu Lab is experienced in the fabrication of microneedle (MN) patches. Our previous studies indicated that MN patch can deliver therapeutics to the tissue effectively. The present R01 proposal represents a logic progression from our previous work while bringing new technologies. Here we will be developing and testing a new entity: a MN-CMMP cardiac patch formed by embedding CMMPs into biodegradable and biocompatible microneedle cardiac patches. In addition, our studies will extend from the previous rodent acute MI model to a chronic MI model in both small/large animals. The overarching hypothesis is that MN-CMMP can further improve the efficacy of CMMP therapy in rats and pigs with chronic heart injury. AIM 1: Fabricate MN-CMMP comprised of microneedle patch loaded with CMMPs; Determine in vitro potency of MN-CMMP in cultured cells. AIM 2: Determine the safety and efficacy of MN-CMMP therapy in rat model of chronic MI. AIM 3: Translate the findings into clinically-relevant porcine models of heart injury. Our study will form the foundation for an innovative and “off the shelf” therapy based on secreted factors and myocardium matrix that can be standardized from donor stem cell lines and xenogenic cardiac tissues. The cell-free nature of our approach is more readily translatable to the clinic. Although this particular grant application targets the heart and cardiac stem cells, our approach represents a platform technology that can be applied to the creation of multiple types of synthetic stem cell and organ matrices for the repair of various other organs.

Date: 04/01/19 - 3/31/23
Amount: $1,534,688.00
Funding Agencies: National Institutes of Health (NIH)

Platelet-endothelial interactions play a vital role in diseases such atherosclerosis and ischemic injury such as myocardial infarction. Vascular injury/inflammation after MI can lead to platelet activation and trafficking, upregulations of adhesion molecules, and production of reactive oxygen and nitrogen species in vasculatures. Despite in many cases platelet activation is harmful, recent studies indicate that after ischemic injury circulating stem cells (release from the bone marrow) rely on platelets to navigate into the injured heart for tissue repair. Platelets form co-aggregates with circulating stem cells in patients with myocardial infarction and thereby increase peripheral recruitment within the ischemic microcirculatory district and promote adhesion to the vascular lesion to promote healing. For the last decade, we have been working in the field of stem cell therapy for post-injury cardiac repair. One big challenge is to target infused stem cells to the cardiac injury site. Poor cell engraftment in the heart may at least partially explain the none-to-marginal efficacy of stem cell therapies for heart diseases so far. We hypothesize that expression of platelet binding motifs on stem cells can help them target to the injured heart. We devised a method of adding platelet binding motifs onto stem cells without genetically altering the cells. Instead, transient expression can be achieved by cell fusion mechanisms. We will first generate platelet membrane vesicles from live platelets and then decorate these vesicles onto the surface of therapeutic stem cells. This method is robust and simple. Under the auspice of this grant study, we aim to evaluate the cytotoxicity of this approach on stem cell functions and test the safety/efficacy of this approach to enhance endogenous and exogenous stem cell therapies in animal models of myocardium infarction.


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