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2. Matrix stiffness modulates the differentiation of neural crest stem cells in vivo

Author

Zhu, Yiqian, Li, Xian, Janairo, Randall Raphael R, Kwong, George, Tsou, Anchi D, Chu, Julia S, Wang, Aijun, Yu, Jian, Wang, Dong, and Li, Song

Subjects
Cardiovascular, Bioengineering, Neurosciences, Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Nonembryonic - Non-Human, Transplantation, Stem Cell Research - Embryonic - Non-Human, Nanotechnology, Stem Cell Research - Embryonic - Human, Biotechnology, Regenerative Medicine, Stem Cell Research, Underpinning research, Development of treatments and therapeutic interventions, 5.2 Cellular and gene therapies, 1.1 Normal biological development and functioning, Animals, Cell Differentiation, Cells, Cultured, Humans, Hydrogels, Induced Pluripotent Stem Cells, Multipotent Stem Cells, Myocytes, Smooth Muscle, Nanofibers, Neural Crest, Neural Stem Cells, Neuroglia, Polymers, Rats, Tissue Engineering, Tissue Scaffolds, glial cells, matrix stiffness, nanofibrous scaffold, neural crest stem cells, smooth muscle cells, vascular tissue engineering, Biochemistry and Cell Biology, Medical Physiology, Biochemistry & Molecular Biology
Abstract

Stem cells are often transplanted with scaffolds for tissue regeneration; however, how the mechanical property of a scaffold modulates stem cell fate in vivo is not well understood. Here we investigated how matrix stiffness modulates stem cell differentiation in a model of vascular graft transplantation. Multipotent neural crest stem cells (NCSCs) were differentiated from induced pluripotent stem cells, embedded in the hydrogel on the outer surface of nanofibrous polymer grafts, and implanted into rat carotid arteries by anastomosis. After 3 months, NCSCs differentiated into smooth muscle cells (SMCs) near the outer surface of the polymer grafts; in contrast, NCSCs differentiated into glial cells in the most part of the hydrogel. Atomic force microscopy demonstrated a stiffer matrix near the polymer surface but much lower stiffness away from the polymer graft. Consistently, in vitro studies confirmed that stiff surface induced SMC genes whereas soft surface induced glial genes. These results suggest that the scaffold's mechanical properties play an important role in directing stem cell differentiation in vivo, which has important implications in biomaterials design for stem cell delivery and tissue engineering.

Published
2019

3. Figure S2. from High-Specificity CRISPR-Mediated Genome Engineering in Anti-BCMA Allogeneic CAR T Cells Suppresses Allograft Rejection in Preclinical Models

Author

Degagné, Émilie, primary, Donohoue, Paul D., primary, Roy, Suparna, primary, Scherer, Jessica, primary, Fowler, Tristan W., primary, Davis, Ryan T., primary, Reyes, Gustavo A., primary, Kwong, George, primary, Stanaway, Morena, primary, Larroca Vicena, Vanina, primary, Mutha, Devin, primary, Guo, Raymond, primary, Edwards, Leslie, primary, Schilling, Benjamin, primary, Shaw, McKay, primary, Smith, Stephen C., primary, Kohrs, Bryan, primary, Kufeldt, Heinrich J., primary, Churchward, Glen, primary, Ruan, Finey, primary, Nyer, David B., primary, McSweeney, Kyle, primary, Irby, Matthew J., primary, Fuller, Christopher K., primary, Banh, Lynda, primary, Toh, Mckenzi S., primary, Thompson, Matthew, primary, Owen, Arthur L.G., primary, An, Zili, primary, Gradia, Scott, primary, Skoble, Justin, primary, Bryan, Mara, primary, Garner, Elizabeth, primary, and Kanner, Steven B., primary

Published
2024
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4. Supplementary Tables from High-Specificity CRISPR-Mediated Genome Engineering in Anti-BCMA Allogeneic CAR T Cells Suppresses Allograft Rejection in Preclinical Models

Author

Degagné, Émilie, primary, Donohoue, Paul D., primary, Roy, Suparna, primary, Scherer, Jessica, primary, Fowler, Tristan W., primary, Davis, Ryan T., primary, Reyes, Gustavo A., primary, Kwong, George, primary, Stanaway, Morena, primary, Larroca Vicena, Vanina, primary, Mutha, Devin, primary, Guo, Raymond, primary, Edwards, Leslie, primary, Schilling, Benjamin, primary, Shaw, McKay, primary, Smith, Stephen C., primary, Kohrs, Bryan, primary, Kufeldt, Heinrich J., primary, Churchward, Glen, primary, Ruan, Finey, primary, Nyer, David B., primary, McSweeney, Kyle, primary, Irby, Matthew J., primary, Fuller, Christopher K., primary, Banh, Lynda, primary, Toh, Mckenzi S., primary, Thompson, Matthew, primary, Owen, Arthur L.G., primary, An, Zili, primary, Gradia, Scott, primary, Skoble, Justin, primary, Bryan, Mara, primary, Garner, Elizabeth, primary, and Kanner, Steven B., primary

Published
2024
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5. Data from High-Specificity CRISPR-Mediated Genome Engineering in Anti-BCMA Allogeneic CAR T Cells Suppresses Allograft Rejection in Preclinical Models

Author

Degagné, Émilie, primary, Donohoue, Paul D., primary, Roy, Suparna, primary, Scherer, Jessica, primary, Fowler, Tristan W., primary, Davis, Ryan T., primary, Reyes, Gustavo A., primary, Kwong, George, primary, Stanaway, Morena, primary, Larroca Vicena, Vanina, primary, Mutha, Devin, primary, Guo, Raymond, primary, Edwards, Leslie, primary, Schilling, Benjamin, primary, Shaw, McKay, primary, Smith, Stephen C., primary, Kohrs, Bryan, primary, Kufeldt, Heinrich J., primary, Churchward, Glen, primary, Ruan, Finey, primary, Nyer, David B., primary, McSweeney, Kyle, primary, Irby, Matthew J., primary, Fuller, Christopher K., primary, Banh, Lynda, primary, Toh, Mckenzi S., primary, Thompson, Matthew, primary, Owen, Arthur L.G., primary, An, Zili, primary, Gradia, Scott, primary, Skoble, Justin, primary, Bryan, Mara, primary, Garner, Elizabeth, primary, and Kanner, Steven B., primary

Published
2024
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6. The Graphs Cases of the Riemannian Positive Mass and Penrose Inequalities in All Dimensions

Author

Lam, Mau-Kwong George

Subjects
Mathematics - Differential Geometry, General Relativity and Quantum Cosmology
Abstract

We consider complete asymptotically flat Riemannian manifolds that are the graphs of smooth functions over $\mathbb R^n$. By recognizing the scalar curvature of such manifolds as a divergence, we express the ADM mass as an integral of the product of the scalar curvature and a nonnegative potential function, thus proving the Riemannian positive mass theorem in this case. If the graph has convex horizons, we also prove the Riemannian Penrose inequality by giving a lower bound to the boundary integrals using the Aleksandrov-Fenchel inequality., Comment: 10 pages, 1 figure

Published
2010

7. Abstract 3201: CB-012, an allogeneic anti-CLL-1 CAR-T cell therapy engineered with next-generation CRISPR technology to resist both the immunosuppressive tumor microenvironment and immune cell-mediated rejection, for patients with relapsed or refractory acute myeloid leukemia

Author

Garner, Elizabeth, primary, Kelly, Erin, additional, Namburi, Sai, additional, Colgan, Cian, additional, Fowler, Tristan, additional, Mutha, Devin, additional, Aviles, Art, additional, Stanaway, Morena, additional, Guo, Raymond, additional, An, Zili, additional, Degagne, Emilie, additional, Kwong, George, additional, Edwards, Leslie, additional, Jakes, Emma, additional, Shaw, McKay, additional, Schilling, Benjamin, additional, Huynh, Jeremy, additional, Luu, Ricky, additional, Sidorov, Max, additional, Mousali, Rhonda, additional, Otsmaa, Mikk, additional, Skoble, Justin, additional, and Kanner, Steven, additional

Published
2023
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8. Allogeneic chimeric antigen receptor-T cells with CRISPR-disrupted programmed death-1 checkpoint exhibit enhanced functional fitness

Author

Lau, Elaine, primary, Kwong, George, additional, Fowler, Tristan W., additional, Sun, Bee-Chun, additional, Donohoue, Paul D., additional, Davis, Ryan T., additional, Bryan, Mara, additional, McCawley, Shannon, additional, Clarke, Starlynn C., additional, Williams, Carolyn, additional, Banh, Lynda, additional, Irby, Matthew, additional, Edwards, Leslie, additional, Storlie, Meghan, additional, Kohrs, Bryan, additional, Lilley, Graham W.J., additional, Smith, Stephen C., additional, Gradia, Scott, additional, Fuller, Chris K., additional, Skoble, Justin, additional, Garner, Elizabeth, additional, van Overbeek, Megan, additional, and Kanner, Steven B., additional

Published
2023
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9. Directed differentiation of mouse pluripotent stem cells into functional lung-specific mesenchyme

Author

Alber, Andrea B., primary, Marquez, Hector A., additional, Ma, Liang, additional, Kwong, George, additional, Thapa, Bibek R., additional, Villacorta-Martin, Carlos, additional, Lindstrom-Vautrin, Jonathan, additional, Bawa, Pushpinder, additional, Luo, Yongfeng, additional, Ikonomou, Laertis, additional, Shi, Wei, additional, and Kotton, Darrell N., additional

Published
2022
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10. CLL-1-Targeted Allogeneic CAR-T Cells Exhibit High on-Target Specificity and Potent Cytotoxicity in Preclinical Models of Acute Myeloid Leukemia

Author

Francica, Brian, Garner, Elizabeth, Namburi, Sai, Colgan, Cian, Fowler, Tristan, Mutha, Devin, Aviles, Art, Stanaway, Morena, Guo, Raymond, An, Zili, Kelly, Erin, Degagne, Emilie, Kwong, George, Edwards, Leslie, Jakes, Emma, Shaw, McKay, Schilling, Benjamin, Huynh, Jeremy, Luu, Ricky, Sidorov, Max, Mousali, Rhonda, Otsmaa, Mikk, Lauer, Peter, Skoble, Justin, and Kanner, Steven

Published
2023
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15. Induced pluripotent stem cell reporter systems for smooth muscle cell sheet engineering

Author

Kwong, George

Subjects
Biomedical engineering
Abstract

Smooth muscle cells exist in many different locations within the body, including blood vessels and airways, where their principal function is contraction and relaxation. The heterogeneity of smooth muscle cells has been related to their embryological origins and could have implications in many diseases, including atherosclerosis, pulmonary hypertension, and asthma. Many of these diseases require an expandable cell source of smooth muscle cells for regenerative medicine or disease modeling. Here, we have developed Acta2hrGFP and ACTA2eGFP (GFP reporters for smooth muscle α-actin) reporter mouse and human induced pluripotent stem cells lines to track and isolate populations of smooth muscle-like cells. iPSCs were patterned to a KDR-expressing (kinase insert domain receptor) mesodermal progenitor, which was further specified towards a smooth muscle-like lineage through exposure to platelet derived growth factor (PDGF-BB) and transforming growth factor (TGF-β). The Acta2hrGFP+ or ACTA2eGFP+ cells were enriched for characteristic markers of smooth muscle cells, and these cells expressed low levels of contractile markers, reminiscent of an immature or synthetic smooth muscle cell. Aligned smooth muscle-like cell sheets were generated using these iPSC-derived populations in an enzymatically degradable hydrogel system. The cell sheets displayed mechanical behavior similar to native blood vessels, with the Acta2hrGFP+ cell sheets displaying a higher ultimate tensile strength than Acta2hrGFP- cell sheets. Furthermore, we performed global transcriptomic profiling of primary adult mouse lung vascular (Acta2hrGFP+ Cspg4DsRed+) and airway (Acta2hrGFP+ Cspg4DsRed-) smooth muscle cells from a double transgenic reporter mouse, where we identified distinct gene signatures of lung vascular SMCs and airway SMCs, with Hhip and Acta2 co-expression distinguishing airway SMCs from lung vascular SMCs. When comparing our miPSC-derived Acta2hrGFP+ cells to these primary SMC signatures, the in vitro derived cells cluster closer to aortic SMCs and lung vascular SMCs, but their transcriptomic signatures still remain significantly distinct. In addition, we have generated an Acta2hrGFP Cspg4DsRed reporter mouse iPSC line, which can be used to understand the signaling pathways involved in specification of these different smooth muscle cell subtypes. Thus, we have developed systems for isolating smooth muscle-like populations which have potential in tissue engineering applications, and we have identified gene signatures of adult lung vascular and airway smooth muscle cells to begin to address the heterogeneity of smooth muscle cell lineages.

Published
2018

16. High-Specificity CRISPR-Mediated Genome Engineering in Anti-BCMA Allogeneic CAR T Cells Suppresses Allograft Rejection in Preclinical Models.

Author

Degagné É, Donohoue PD, Roy S, Scherer J, Fowler TW, Davis RT, Reyes GA, Kwong G, Stanaway M, Larroca Vicena V, Mutha D, Guo R, Edwards L, Schilling B, Shaw M, Smith SC, Kohrs B, Kufeldt HJ, Churchward G, Ruan F, Nyer DB, McSweeney K, Irby MJ, Fuller CK, Banh L, Toh MS, Thompson M, Owen ALG, An Z, Gradia S, Skoble J, Bryan M, Garner E, and Kanner SB

Subjects
Humans, B-Cell Maturation Antigen metabolism, HLA-E Antigens, T-Lymphocytes, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive, Histocompatibility Antigens Class I metabolism, Allografts pathology, Multiple Myeloma genetics, Multiple Myeloma therapy, Hematopoietic Stem Cell Transplantation
Abstract

Allogeneic chimeric antigen receptor (CAR) T cell therapies hold the potential to overcome many of the challenges associated with patient-derived (autologous) CAR T cells. Key considerations in the development of allogeneic CAR T cell therapies include prevention of graft-vs-host disease (GvHD) and suppression of allograft rejection. Here, we describe preclinical data supporting the ongoing first-in-human clinical study, the CaMMouflage trial (NCT05722418), evaluating CB-011 in patients with relapsed/refractory multiple myeloma. CB-011 is a hypoimmunogenic, allogeneic anti-B-cell maturation antigen (BCMA) CAR T cell therapy candidate. CB-011 cells feature 4 genomic alterations and were engineered from healthy donor-derived T cells using a Cas12a CRISPR hybrid RNA-DNA (chRDNA) genome-editing technology platform. To address allograft rejection, CAR T cells were engineered to prevent endogenous HLA class I complex expression and overexpress a single-chain polyprotein complex composed of beta-2 microglobulin (B2M) tethered to HLA-E. In addition, T-cell receptor (TCR) expression was disrupted at the TCR alpha constant locus in combination with the site-specific insertion of a humanized BCMA-specific CAR. CB-011 cells exhibited robust plasmablast cytotoxicity in vitro in a mixed lymphocyte reaction in cell cocultures derived from patients with multiple myeloma. In addition, CB-011 cells demonstrated suppressed recognition by and cytotoxicity from HLA-mismatched T cells. CB-011 cells were protected from natural killer cell-mediated cytotoxicity in vitro and in vivo due to endogenous promoter-driven expression of B2M-HLA-E. Potent antitumor efficacy, when combined with an immune-cloaking armoring strategy to dampen allograft rejection, offers optimized therapeutic potential in multiple myeloma. See related Spotlight by Caimi and Melenhorst, p. 385., (©2024 The Authors; Published by the American Association for Cancer Research.)

Published
2024
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