Publications by authors named "Stephen P Ma"

7 Publications

  • Page 1 of 1

Bioengineered optogenetic model of human neuromuscular junction.

Biomaterials 2021 09 30;276:121033. Epub 2021 Jul 30.

Columbia University, 622 W 168th St, New York, NY, 10032, USA. Electronic address:

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 therapeutic targets and treatments for patients with complex central and peripheral nervous system disorders. There is a need to develop standardized and objective quantitative methods for engineering and using these complex tissues, in order increase their robustness, reproducibility, and predictiveness across users. Here we describe a standardized method for engineering an isogenic, patient specific human neuromuscular junction (NMJ) that allows for automated quantification of NMJ function to diagnose disease using a small sample of blood serum and evaluate new therapeutic modalities. By combining tissue engineering, optogenetics, microfabrication, optoelectronics and video processing, we created a novel platform for the precise investigation of the development and degeneration of human NMJ. We demonstrate the utility of this platform for the detection and diagnosis of myasthenia gravis, an antibody-mediated autoimmune disease that disrupts the NMJ function.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439334PMC
September 2021

Author Correction: Advanced maturation of human cardiac tissue grown from pluripotent stem cells.

Nature 2019 Aug;572(7769):E16-E17

Department of Biomedical Engineering, Columbia University, New York, NY, USA.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41586-019-1415-9DOI Listing
August 2019

Quantification of human neuromuscular function through optogenetics.

Theranostics 2019 31;9(5):1232-1246. Epub 2019 Jan 31.

Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA.

The study of human neuromuscular diseases has traditionally been performed in animal models, due to the difficulty of performing studies in human subjects. Despite the unquestioned value of animal models, inter-species differences hamper the translation of these findings to clinical trials. Tissue-engineered models of the neuromuscular junction (NMJ) allow for the recapitulation of the human physiology in tightly controlled settings. : Here we report the first human patient-specific tissue-engineered model of the neuromuscular junction (NMJ) that combines stem cell technology with tissue engineering, optogenetics, microfabrication and image processing. The combination of custom-made hardware and software allows for repeated, quantitative measurements of NMJ function in a user-independent manner. : We demonstrate the utility of this model for basic and translational research by characterizing in real time the functional changes during physiological and pathological processes. : This system holds great potential for the study of neuromuscular diseases and drug screening, allowing for the extraction of quantitative functional data from a human, patient-specific system.
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http://dx.doi.org/10.7150/thno.25735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401498PMC
January 2020

Dual IFN-γ/hypoxia priming enhances immunosuppression of mesenchymal stromal cells through regulatory proteins and metabolic mechanisms.

J Immunol Regen Med 2018 Mar 25;1:45-56. Epub 2018 Apr 25.

Department of Biomedical Engineering, Columbia University, New York, NY, USA.

The immunosuppressive capacity of human mesenchymal stromal cells (MSCs) renders them promising candidates for treating diverse immune disorders. However, after hundreds of clinical trials, there are still no MSC therapies approved in the United States. MSCs require specific cues to adopt their immunosuppressive phenotype, and yet most clinical trials use cells expanded in basic culture medium and growth conditions. We propose that priming MSCs prior to administration will improve their therapeutic efficacy. Interferon-gamma (IFN-γ) priming are cues common to situations of immune escape that have individually shown promise as MSC priming cues but have not been systematically compared. Using mixed lymphocyte reactions, we show that priming MSCs with either cue alone improves T-cell inhibition. However, combining the two cues results in additive effects and markedly enhances the immunosuppressive phenotype of MSCs. We demonstrate that IFN-γ induces expression of numerous immunosuppressive proteins (IDO, PD-L1, HLA-E, HLA-G), whereas hypoxia switches MSCs to glycolysis, causing rapid glucose consumption and production of T-cell inhibitory lactate levels. Dual IFN-γ/hypoxia primed MSCs display both attributes and have even higher induction of immunosuppressive proteins over IFN-γ priming alone (IDO and HLA-G), which may reflect another benefit of metabolic reconfiguration.
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http://dx.doi.org/10.1016/j.regen.2018.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197483PMC
March 2018

Advanced maturation of human cardiac tissue grown from pluripotent stem cells.

Nature 2018 04 4;556(7700):239-243. Epub 2018 Apr 4.

Laboratory for Stem Cells and Tissue Engineering, Department of Biomedical Engineering, Columbia University, New York, NY, USA.

Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease. However, the predictive power of these models is presently limited by the immature state of the cells. Here we show that this fundamental limitation can be overcome if cardiac tissues are formed from early-stage iPSC-derived cardiomyocytes soon after the initiation of spontaneous contractions and are subjected to physical conditioning with increasing intensity over time. After only four weeks of culture, for all iPSC lines studied, such tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiological sarcomere length (2.2 µm) and density of mitochondria (30%), the presence of transverse tubules, oxidative metabolism, a positive force-frequency relationship and functional calcium handling. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiological responses to isoproterenol and recapitulating pathological hypertrophy, supporting the utility of this tissue model for studies of cardiac development and disease.
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http://dx.doi.org/10.1038/s41586-018-0016-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895513PMC
April 2018

Real-Time Bioluminescence Imaging of Cell Distribution, Growth, and Differentiation in a Three-Dimensional Scaffold Under Interstitial Perfusion for Tissue Engineering.

Tissue Eng Part C Methods 2016 09 10;22(9):864-72. Epub 2016 Aug 10.

2 Cell Therapy Group, Catalonian Institute for Advanced Chemistry (IQAC-CSIC), Barcelona, Spain .

Bioreactor systems allow safe and reproducible production of tissue constructs and functional analysis of cell behavior in biomaterials. However, current procedures for the analysis of tissue generated in biomaterials are destructive. We describe a transparent perfusion system that allows real-time bioluminescence imaging of luciferase expressing cells seeded in scaffolds for the study of cell-biomaterial interactions and bioreactor performance. A prototype provided with a poly(lactic) acid scaffold was used for "proof of principle" studies to monitor cell survival in the scaffold (up to 22 days). Moreover, using cells expressing a luciferase reporter under the control of inducible tissue-specific promoters, it was possible to monitor changes in gene expression resulting from hypoxic state and endothelial cell differentiation. This system should be useful in numerous tissue engineering applications, the optimization of bioreactor operation conditions, and the analysis of cell behavior in three-dimensional scaffolds.
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http://dx.doi.org/10.1089/ten.TEC.2014.0421DOI Listing
September 2016

Tissue-Engineering for the Study of Cardiac Biomechanics.

J Biomech Eng 2016 Feb;138(2):021010

The notion that both adaptive and maladaptive cardiac remodeling occurs in response to mechanical loading has informed recent progress in cardiac tissue engineering. Today, human cardiac tissues engineered in vitro offer complementary knowledge to that currently provided by animal models, with profound implications to personalized medicine. We review here recent advances in the understanding of the roles of mechanical signals in normal and pathological cardiac function, and their application in clinical translation of tissue engineering strategies to regenerative medicine and in vitro study of disease.
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http://dx.doi.org/10.1115/1.4032355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845250PMC
February 2016
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