Abstract: The present disclosure is directed to systems, methods, and compositions for functional interaction of fibroblasts with one or more types of immune cells such that the interaction results in modification to the fibroblasts, the one or more types of immune cells, or both. In some embodiments, one or more certain agents are also utilized during the interaction or in lieu of one of the types of cells. In specific embodiments, cells to be used in cellular transplantation therapy are modified to have reduced immunogenicity.

Abstract: Disclosed are means and compositions of matter for treating degenerative disc disease and associated pain in part by stimulating enhanced local perfusion and reduction of inflammation. In one embodiment administration of inducible pluripotent stem cell derived mesenchymal stem cells is performed wherein said cells are optimized for migration and/or retention into perispinal environment. In some embodiments said mesenchymal stem cells are optimized for enhanced angiogenesis and/or suppression of inflammation. In another embodiment inducible pluripotent stem cell derived T regulatory cells are administered alone or with said mesenchymal stem cells in order to elicit enhanced perispinal perfusion while concurrently reducing inflammation.

Abstract: Methods and compositions of matter for production of pancreatic beta cells, as well as beta-like cells that are capable of producing insulin. Pluripotent stem cells are generated through either viral vector or non-viral vector means and induced into differentiation pathways through environments resembling the pluripotent pancreatic environment. In vivo transfection of dedifferentiation and beta cell differentiation genes are provided in vivo in the pancreatic microenvironment to generate de novo beta cells and islets from differentiated tissue or islet progenitors. Means of inducing differentiation of islet progenitors in vivo are also provided.

Abstract: Compositions of matter and therapeutic means for stimulation bone, cartilage or joint regeneration by pluripotent stem cell derived mesenchymal stem cells alone or in a manipulated manner. “Semidifferentiated” mesenchymal stem cells which possess enhanced ability to generate cartilage, bone, or joint tissue. Gene editing is utilized to generate cells with reduced immunogenicity and enhanced therapeutic potential. Enhancement of therapeutic activity is achieved by transfection of pluripotent stem cells with genes which inhibit apoptosis, thus enhancing lifespan and therapeutic activity of said stem cells. Transfection with antioxidant genes such as superoxide dismutase is utilized to enhance activity of cells when administered in inflammatory environments.

Abstract: The present disclosure is directed to systems, methods, and compositions for functional interaction of fibroblasts with one or more types of immune cells such that the interaction results in modification to the fibroblasts, the one or more types of immune cells, or both. In some embodiments, one or more certain agents are also utilized during the interaction or in lieu of one of the types of cells. In specific embodiments, cells to be used in cellular transplantation therapy are modified to have reduced immunogenicity.

Abstract: Compositions of matter and methods of treatment based on generation of T cells capable of ameliorating or treating pathologies associated with improper immune activation. Chimeric antigen receptor (CAR) T cells are generated which possess tolerogenic properties based on enhanced expression of NR2F6. NR2F6 is enhanced through transfection of cells with a modified siRNA sequence. NR2F6 expression is upregulated through tissue culture modification, and NR2F6 expression vectors are introduced to the cell of interest. Methods and compositions to treat autoimmunity, transplant rejection, and conditions associated with pathological immune activation.

Abstract: Methods and compositions of matter useful for reducing extent of spinal cord injury and/or reversion of spinal cord injury gliosis are disclosed. T regulatory cells can be administered systemically and/or locally to a patient suffering from spinal cord injury. T regulatory cells can be modulated by engineering either through gene modification or culture conditions in order to augment regenerative/antifibrotic properties. Utilizing pluripotent stem cell derived T regulatory cells for spinal cord injury and chimeric antigen receptor T cells.

Abstract: Compositions of matter and treatment protocols for reducing or completely avoiding the need for immune suppression in the context of allograft or xenograft transplantation. Use of mesenchymal stem cells, manipulated mesenchymal stem cells, iPSC derived mesenchymal stem cells, and products of said mesenchymal stem cells for promoting the process of immunological tolerance. In one embodiment the invention provides the use of third party “universal donor” iPSC gene edited mesenchymal stem cells to promote tolerance in context of a solid organ transplant such as renal, cardiac, hepatic or small intestine. In other embodiments endogenous mesenchymal stem cells in composite tissue allografts are activated and/expanded in order to promote tolerogenesis and reduced need for immune suppression.

Abstract: Disclosed are compositions and methods of treating muscular dystrophies, including Duchenne Muscular Dystrophy (DMD) through administration of fibroblasts and modified fibroblasts systemically and locally. In certain embodiments, fibroblast cells are utilized for replacement of dystrophin through fusion and/or other means of horizontal gene transfer. In other embodiments, the disclosure teaches the use of fibroblasts for reduction of inflammatory reactions and/or immunological reactions which propagate and enhance myodestructive aspects of Duchenne Muscular Dystrophy. In other embodiments, fibroblasts are utilized as vectors for gene therapy and/or gene modifications approaches.

Abstract: Disclosed are methods and compositions comprising fibroblasts and/or products derived thereof for the inhibition and/or treatment of addiction of any kind, such as opioid addiction. In some embodiments, methods comprise treating a patient addicted to opioids by administering a fibroblast population at a concentration sufficient for suppression of addiction-associated brain damage. In some embodiments, the fibroblasts express CD31 and/or CD73 markers. In some embodiments, fibroblasts are used to endow neuronal regeneration in order to overcome changes in the brain associated with addiction. Some embodiments relate to the stimulation of hippocampal regeneration subsequent to addiction induced damage.

Abstract: Compositions of matter and means useful for treatment of autoimmunity and/or transplant rejection through generation of T regulatory cells in a manner that recapitulates thymic development. Methods of seeding thymic medullary epithelial cells with pluripotent stem cells such as inducible pluripotent stem cells, followed by exposure to conditions allowing for selective growth and expansion of T regulatory cells. T regulatory cells can be scaled for clinical utilization through the use of three-dimensional adhesive growth matrices as well as addition of FoxP3 inducing cytokines such as interleukin-2.

Abstract: Cellular modifications useful for enhancing migratory potential of T regulatory cells that have been derived from inducible pluripotent stem cells. In one embodiment said inducible pluripotent stem cells are gene edited for insertion or deletion of cytoskeletal and motility associated genes in order to increase migration ability as well as deformability of cells in a manner allowing for increased extravasation and mobility. In other embodiments inducible pluripotent stem cell derived T regulatory cells are gene edited at the level of T Regulatory cell progenitor stage.

Abstract: The invention provides methods of inducing immunological tolerance to a transplanted cellular population or organ by creating and administering a “veto-like” cell originating from the identical genetic background of the organ donor. In one embodiment said artificially generated veto cell is a dendritic cell population possessing molecules associated with tolerance induced in natural anatomical locations such as the placenta, the testis, or the eye. In one embodiment dendritic cells resistant to maturation are generated from pluripotent stem cells that have been gene edited to lack genes needed for acquisition of antigen presenting properties such as relB, NF-kappa B and transporter associated protein. In another embodiment immature dendritic cells are gene edited/transfected to express tolerance associated molecules such as interleukin-10, interleukin-35, Fas ligand, TRAIL, TGF-beta, HLA-G and arginase.

Abstract: The present disclosure provides means of inhibition and/or treating aneurysms and other degenerated blood vessels through administration of regenerative cell derived exosomes, and/or regenerative cell derived apoptotic bodies. In one particular embodiment vessel regeneration is increased through administration of stem cell exosomes/or stem cell apoptotic bodies. Other embodiments include regeneration of vessels prone to aneurysms, repairing aneurysms of vessels, or acceleration of endothelialization after stent placement. Provided within the invention are methods of rejuvenating properties of said vessels associated with physiological health, examples of which include appropriate production of anti-coagulating/clotting factors, control of angiogenesis, and appropriate revascularization of injured tissue.

Abstract: Disclosed are methods and means of optimizing health of a subject during space travel comprising real time monitoring and intervention guided by automated and/or semiautomated means driven by a machine learning artificial intelligence-based system. In one embodiment the invention discloses the integration of genetic factors, biological properties, microbiome diversity, regenerative activity, and real time physiological changes in order to provide optimum interventions which result in increased health upon return from the space mission, as well as provide ability for said astronaut to endure space travel of increased durations.

Abstract: Disclosed are means, methods and compositions of matter useful for stimulation of immunity to tumor antigens through isolation of dendritic cell exosomes from dendritic cells that have been pulsed with said tumor antigens and/or pulsed dendritic cells that have been gene silenced/gene edited for immune suppressive genes. In one embodiment said tumor antigen is survivin and said immune suppressive genes include interleukin-10, interleukin-35, TGF-beta and interleukin-13. In some embodiments dendritic cells are further transfected with immune stimulatory genes including interleukin-2, interleukin?12, interleukin-15 and interleukin-18.

Abstract: Disclosed are methods and compositions comprising fibroblasts and/or products derived thereof for the inhibition and/or treatment of addiction of any kind, such as opioid addiction. In some embodiments, methods comprise treating a patient addicted to opioids by administering a fibroblast population at a concentration sufficient for suppression of addiction-associated brain damage. In some embodiments, the fibroblasts express CD31 and/or CD73 markers. In some embodiments, fibroblasts are used to endow neuronal regeneration in order to overcome changes in the brain associated with addiction. Some embodiments relate to the stimulation of hippocampal regeneration subsequent to addiction induced damage.

Abstract: Disclosed are means of generating organs or organoids utilizing three-dimensional bio-printing processes. In one embodiment said organ is a pancreas or pancreas-like organ useful for the treatment of diabetes, wherein said bioprinted pancreas possesses enhanced regenerative activity, in some embodiments comparable to the liver due to seeding with enhanced numbers of regenerative cells. In another embodiment pancreatic islets are created capable of being utilized as a substitute for naturally occurring islets. In other embodiments immune-evasive organs are created utilizing combination of cells which possess ability to evade immunity, thus allowing for tolerance induction without need for immune suppressive activity.

Abstract: Disclosed are systems, means and compositions of matter utilizing artificial intelligence to create unique cells and/or organs from pluripotent stem cells. In one embodiment an artificial intelligence/machine learning approach is utilized to overview and categorize molecular and cellular data regarding normal embryonic development and associated pathways. Through acquiring this information, said artificial intelligence/machine learning system develops a graded list of morphogens/differentiating agents and/or conditions that are utilized to replicate the process of cell/tissue/organ formation artificially. In one embodiment the invention teaches generation of artificial pancreatic organoids through growth factors predicted by said artificial intelligence/machine learning systems. In other embodiments embryogenesis is recapitulated in adult tissue using predicted morphogens and/or extracellular matrix treatments.

Abstract: Disclosed are methods, means and systems of identifying compounds and augment T regulatory cell activity and/or number in vitro and/or in vivo utilizing deep learning approaches. Systems for screening compound libraries in silico are provided as well as laboratory methods of testing modulation of T regulatory cell activity and/or numbers. Results provided by the disclosure will serve as the basis for increasing T regulatory cells, which is desirable in situations of autoimmunity or organ transplantation. In situations of oncology or infectious disease reduction of T regulatory cell number and/or activity is desired.