Delivery of Immobilized IFN-γ With PCN-333 and Its Effect on Human Mesenchymal Stem Cells.

Interferon-gamma (IFN-γ) plays a vital role in modulating the immunosuppressive properties of human mesenchymal stem/stromal cells (hMSCs) used in cell therapies. However, IFN-γ suffers from low bioavailability and degrades in media, creating a challenge when using IFN-γ during the manufacturing of hMSCs. Metal-organic frameworks (MOFs), with their porous interiors, biocompatibility, high loading capacity, and ability to be functionalized for targeting, have become an increasingly suitable platform for protein delivery. In this work, we synthesize the MOF PCN-333(Fe) and show that it can be utilized to immobilize and deliver IFN-γ to the local extracellular environment of hMSCs. In doing so, the cells proliferate and differentiate appropriately with no observed side effects. We demonstrate that PCN-333(Fe) MOFs containing IFN-γ are not cytotoxic to hMSCs, can promote the expression of proteins that play a role in immune response, and are capable of inducing indoleamine 2,3-dioxygenase (IDO) production similar to that of soluble IFN-γ at lower concentrations. Overall, using MOFs to deliver IFN-γ may be leveraged in the future in the manufacturing of therapeutically relevant hMSCs.

[1]  Luis Pinzon-Herrera,et al.  Immunomodulatory functions of human mesenchymal stromal cells are enhanced when cultured on HEP/COL multilayers supplemented with interferon-gamma , 2021, Materials today. Bio.

[2]  Brian J. Kwee,et al.  Functional heterogeneity of IFN-γ–licensed mesenchymal stromal cell immunosuppressive capacity on biomaterials , 2021, Proceedings of the National Academy of Sciences.

[3]  R. Mishra,et al.  Sivelestat-loaded nanostructured lipid carriers modulate oxidative and inflammatory stress in human dental pulp and mesenchymal stem cells subjected to oxygen-glucose deprivation. , 2020, Materials science & engineering. C, Materials for biological applications.

[4]  V. Lang,et al.  Intracellular role of IL-6 in mesenchymal stromal cell immunosuppression and proliferation , 2020, Scientific Reports.

[5]  L. Arriaga-Pizano,et al.  Human Bone Marrow Mesenchymal Stem/Stromal Cells Exposed to an Inflammatory Environment Increase the Expression of ICAM-1 and Release Microvesicles Enriched in This Adhesive Molecule: Analysis of the Participation of TNF-α and IFN-γ , 2020, Journal of immunology research.

[6]  S. R. Wickramasinghe,et al.  Methods for the Assembly and Characterization of Polyelectrolyte Multilayers as Microenvironments to Modulate Human Mesenchymal Stromal Cell Response. , 2020, ACS biomaterials science & engineering.

[7]  David A. Castilla-Casadiego,et al.  Heparin/Collagen Surface Coatings Modulate the Growth, Secretome and Morphology of Human Mesenchymal Stromal Cell Response to Interferon-Gamma. , 2020, Journal of biomedical materials research. Part A.

[8]  M. H. Beyzavi,et al.  Catalytic Activity, Stability, and Loading Trends of Alcohol Dehydrogenase Enzyme Encapsulated in a Metal-Organic Framework. , 2020, ACS applied materials & interfaces.

[9]  M. Pittenger,et al.  Mesenchymal stem cell perspective: cell biology to clinical progress , 2019, npj Regenerative Medicine.

[10]  Ana M Reyes-Ramos,et al.  Effects of Physical, Chemical, and Biological Stimulus on h-MSC Expansion and Their Functional Characteristics , 2019, Annals of Biomedical Engineering.

[11]  Andrés J. García,et al.  IFN-γ-tethered hydrogels enhance mesenchymal stem cell-based immunomodulation and promote tissue repair. , 2019, Biomaterials.

[12]  Andrés J. García,et al.  Heparin/Collagen Coatings Improve Human Mesenchymal Stromal Cell Response to Interferon Gamma. , 2019, ACS biomaterials science & engineering.

[13]  M. Nireekshan Kumar,et al.  Gelatin-Coated Polycaprolactone Nanoparticle-Mediated Naringenin Delivery Rescue Human Mesenchymal Stem Cells from Oxygen Glucose Deprivation-Induced Inflammatory Stress. , 2018, ACS biomaterials science & engineering.

[14]  J. Gassensmith,et al.  Enhanced Stability and Controlled Delivery of MOF-Encapsulated Vaccines and Their Immunogenic Response In Vivo. , 2018, ACS applied materials & interfaces.

[15]  Zhongyu Yang,et al.  How Do Enzymes Orient When Trapped on Metal-Organic Framework (MOF) Surfaces? , 2018, Journal of the American Chemical Society.

[16]  Diego A. Gómez-Gualdrón,et al.  Hierarchically Engineered Mesoporous Metal-Organic Frameworks toward Cell-free Immobilized Enzyme Systems , 2018 .

[17]  J. K. Leach,et al.  Materials-Directed Differentiation of Mesenchymal Stem Cells for Tissue Engineering and Regeneration. , 2017, ACS biomaterials science & engineering.

[18]  Hong‐Cai Zhou,et al.  High efficiency and long-term intracellular activity of an enzymatic nanofactory based on metal-organic frameworks , 2017, Nature Communications.

[19]  Ross A. Marklein,et al.  Morphological features of IFN-γ–stimulated mesenchymal stromal cells predict overall immunosuppressive capacity , 2017, Proceedings of the National Academy of Sciences.

[20]  Joshua A. Zimmermann,et al.  Enhanced Immunosuppression of T Cells by Sustained Presentation of Bioactive Interferon‐γ Within Three‐Dimensional Mesenchymal Stem Cell Constructs , 2016, Stem cells translational medicine.

[21]  N. Puig,et al.  MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry , 2016, Cell Communication and Signaling.

[22]  Jihye Park,et al.  Dual Exchange in PCN-333: A Facile Strategy to Chemically Robust Mesoporous Chromium Metal-Organic Framework with Functional Groups. , 2015, Journal of the American Chemical Society.

[23]  W. Langridge,et al.  The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity , 2015, Vaccines.

[24]  Yifei Zhang,et al.  Enhanced Activity of Immobilized or Chemically Modified Enzymes , 2015 .

[25]  N. Roher,et al.  Synthesis, culture medium stability, and in vitro and in vivo zebrafish embryo toxicity of metal-organic framework nanoparticles. , 2015, Chemistry.

[26]  Zhenjie Zhang,et al.  Why does enzyme not leach from metal-organic frameworks (MOFs)? Unveiling the interactions between an enzyme molecule and a MOF. , 2014, Inorganic chemistry.

[27]  Michael O’Keeffe,et al.  The Chemistry and Applications of Metal-Organic Frameworks , 2013, Science.

[28]  Fiona M. Watt,et al.  Role of the extracellular matrix in regulating stem cell fate , 2013, Nature Reviews Molecular Cell Biology.

[29]  M. Brizzi,et al.  Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. , 2012, Current opinion in cell biology.

[30]  S. Shi,et al.  Mesenchymal Stem Cell-Based Tissue Regeneration is Governed by Recipient T Lymphocyte via IFN-γ and TNF-α , 2011, Nature Medicine.

[31]  Kazuo Suzuki,et al.  Interferon-γ Regulates the Proliferation and Differentiation of Mesenchymal Stem Cells via Activation of Indoleamine 2,3 Dioxygenase (IDO) , 2011, PloS one.

[32]  Richard O. Hynes,et al.  The Extracellular Matrix: Not Just Pretty Fibrils , 2009, Science.

[33]  H. Lortat-Jacob,et al.  The molecular basis and functional implications of chemokine interactions with heparan sulphate. , 2009, Current opinion in structural biology.

[34]  Omar M Yaghi,et al.  The pervasive chemistry of metal-organic frameworks. , 2009, Chemical Society reviews.

[35]  Michael O'Keeffe,et al.  Secondary building units, nets and bonding in the chemistry of metal-organic frameworks. , 2009, Chemical Society reviews.

[36]  K. Atkinson,et al.  Therapeutic applications of mesenchymal stromal cells. , 2007, Seminars in cell & developmental biology.

[37]  Michael O'Keeffe,et al.  Hydrogen Storage in Microporous Metal-Organic Frameworks , 2003, Science.

[38]  Michael O'Keeffe,et al.  Systematic Design of Pore Size and Functionality in Isoreticular MOFs and Their Application in Methane Storage , 2002, Science.

[39]  T. Reineke,et al.  Assembly of metal-organic frameworks from large organic and inorganic secondary building units: new examples and simplifying principles for complex structures. , 2001, Journal of the American Chemical Society.

[40]  H Li,et al.  Modular chemistry: secondary building units as a basis for the design of highly porous and robust metal-organic carboxylate frameworks. , 2001, Accounts of chemical research.

[41]  Mohamed Eddaoudi,et al.  Highly Porous and Stable Metal−Organic Frameworks: Structure Design and Sorption Properties , 2000 .

[42]  U. Hadding,et al.  A new, simple, bioassay for human IFN-γ , 1994 .