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Ke Cheng

Unpaid Research Scholar

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: 09/01/19 - 7/31/24
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: 07/01/21 - 6/30/24
Amount: $692,854.00
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 - 5/31/24
Amount: $740,541.00
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: 04/01/21 - 3/31/24
Amount: $2,278,395.00
Funding Agencies: National Institutes of Health (NIH)

Numerous studies indicate that adult stem cells exert their functional benefits mainly through paracrine effects, i.e., secreted factors from stem cells promote cardiac regeneration and inhibit fibrosis and inflammation. However, two major challenges remain to efficiently delivery stem cell factors to the injured myocardium: 1) injected growth factors are quickly diffused, therefore sustained release is needed; 2) local injection is effective but requires open chest procedure, systemic injection is safe but cannot get sufficient dosage to the heart, therefore targeted delivery is needed. To overcome those challenges, we designed a platelet-inspired nano-cell (PINC) that has a core containing stem cell factors and a platelet membrane shell for injury binding. The core consists of therapeutic CSC-secreted factors encapsulated in a biodegradable poly (lactic-co-glycolic acid) (PLGA) nanoparticle for sustained release. The platelet membrane is conjugated with PGE2 which is expected to have targetability to cardiovascular cells and facilitate the endogenous repair through PGE2/EP receptor signaling after I/R injury. As a novel biomimetic therapeutic nanoparticle, PINC offers the following advantages compared to natural stem cells: (i) PINC is small enough for systemic administration: the nano size of PINC enables intravenous application; unlike stem cells, PINCs are less likely to be blocked by the lungs; (ii) PINC has dual targeting ability: the platelet membrane on PINCs targets injured blood vessels while the PGE2 targets injured cardiomyocytes in MI; (iii) PINC is stable during storage: unlike real stem cells, PINCs can be readily manipulated and cryopreserved since there are no living components. The Specific Aims are: AIM 1. Fabricate PINC particles functionalized with PGE2 and CSC secretome; Test the in vitro potency and cytotoxicity of PINC; AIM 2. Determine the safety, efficacy, and mechanism of PINC therapy in a rat model of ischemia-reperfusion (IR) injury; AIM 3. Translate the findings into a clinically-relevant porcine model of IR injury. Our study will form the foundation for an innovative and “off the shelf” therapy based on secreted factors and targeted nanomedicine that can be standardized from donor stem cell lines and xenogeneic 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: 04/20/20 - 3/31/24
Amount: $3,026,009.00
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: 04/01/20 - 3/31/24
Amount: $2,935,224.00
Funding Agencies: National Institutes of Health (NIH)

Currently, ischemic damage to the heart cannot be repaired by conventional medical care therefore only palliative treatments exist. Stem cell transplantation is a promising strategy for therapeutic cardiac regeneration, but current therapies are limited by insufficient interaction between the regenerative cells and the injured tissue. In the last grant period, we have developed targeted nanoparticles (namely bispecific antibody-conjugated agents) to redirect circulating stem cells to the infarcted heart for therapeutic regeneration. Despite such initial success, we realize our system has some problems: (P1) We cannot fully reply on the stem cells (“seeds”) for cardiac repair. The post-injury heart microenvironment (“soil”) needs to be primed for the maximum outcome; (P2) Antibody targeting is quite specific but is fully dependent on the antigen, which are cardiac injury biomarkers that only expresses in a short period of time after injury. The current renewal proposal builds on the previous study, but represents a significant advancement, both technically and conceptually. To address P1, we reason one of the antibodies needs to be therapeutic, to combat the excessive inflammation in the heart. To address P2, we seek for agents that have broad spectrum affinity with cardiac injury. To those ends, we developed anti-IL-1 platelet mimetic (IL1-PM). The mode of action for IL1-PM is as follows: platelet vesicles serve as the carrier of our system and they have innate ability to find cardiac injury (replying on the binding motifs on platelet membranes); anti-IL-1 antibodies are currently in Phase 3 clinical trials and have demonstrated ability to neutralize inflammation and promote cardiac repair; platelet vesicles can be further loaded with stem cell-derived growth factors to aid the repair process. AIM 1: Fabricate IL1-PM and characterize its physicochemical and biological properties. We will generate IL1-PM agents by conjugating anti IL-1 antibodies onto platelet membrane nanovesicles; binding/engaging ability, toxicity, pharmacokinetics of IL1-PM will be examined in cultured cells and in healthy animals. AIM 2: Determine the therapeutic potential of mesenchymal stem cell (MSC) secretome-loaded IL1-PM in a mouse model of myocardial infarction. MI will be induced by ischemia-reperfusion. After that, MSC-IL1-PM, along with various control agents, will be delivered intravenously. Therapeutic safety and efficacy will be determined. In addition,the underlying mechanisms of such treatment will be explored. AIM 3: Translate the findings into a clinically-relevant large animal model of myocardial infarction. MI will be induced in swine via a balloon-occlusion procedure. The safety and efficacy of MSC-IL1-PM treatment will be evaluated. Our therapeutic system combines stem cell therapy (component 1) and anti-IL1 therapy (component 2), both of which have been rigorously tested and verified in clinical trials for cardiac repair. Moreover, the therapeutics will be delivered in a targetable fashion relying on the injury-finding ability of platelet binding motifs (component 3). All 3 components have been supported by strong preliminary data from our group.

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: 04/01/19 - 3/31/24
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.

Date: 04/01/19 - 3/31/24
Amount: $1,520,000.00
Funding Agencies: National Institutes of Health (NIH)

It has been established that most of the beneficial effects of transplanted cells are indirect: injected cells secrete paracrine factors that promote endogenous heart repair. Among those secreted substances, exosomes are 30-100 nm vesicles secreted by a wide range of cell types including tumor cells and stem cells. Exosomes can transport microRNAs (miRs) that enable cells to communicate with neighboring cells to change their behavior. The essential miR cargos underlying the therapeutic potencies of exosomes have yet to be determined. In addition, unlike stem cells, exosomes do not have migratory ability therefore local injections are performed to ensure delivery. However, direction injection into the heart is not trivial, normally requiring open-chest surgery or sophisticated endomyocardial injection setups such as the NOGA mapping system. It is crucial to develop techniques to target systemically delivered exosomes to the heart injury. Our long-term goal is to create exosomes with optimized cargos and surfaces for precision cardiac repair. In our preliminary studies, we compared cultured cardiac stromal cells from normal and failing human hearts, and isolated exosomes from these cells. In vitro experiments and animal studies indicate an impaired regenerative activity of exosomes from heart failure patients. In addition, miR array revealed dysregulation of miR-21 in heart failure exosomes. Based on those preliminary results, we hypothesize that: i) there is a loss of therapeutic properties in exosomes from heart failure and such functional loss is due to alterations in repertoire miRs such as miR-21; ii) modulating such miR cargos could rescue the regenerative potential of the diseased exosomes; iii) efficient systemic delivery and injury targeting can be achieved by exosomal surface modification. Studies proposed in this proposal are highly significant since they aim to enhance our fundamental understating of mechanisms underlying exosomes’ reparative function but may also pave the way for future clinical translation.


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