Abstract: Embodiments of the disclosure include methods and compositions for use of prepared fibroblasts and/or conditioned media therefrom. In particular embodiments, the prepared fibroblasts have enhanced regenerative and may have an increase in secretion of one or more cytokines and/or growth factors; may have an increase in anti-apoptotic activity; and/or may have a modulated immunogenicity. In specific embodiments, the fibroblasts are prepared by exposure to hypoxia and/or carbon monoxide.

Abstract: Disclosed are novel means of enhancing efficacy of pancreatic islet transplantation through administration of regenerative T cells concurrently with modification of the local microenvironment to provide a tolerogenic and angiogenic milieu. In one embodiment, the liver microenvironment is prepared for receipt of pancreatic islets by administration of tolerogenic cells antigen presenting cells, subsequently followed by administration of T cells and/or T regulatory cells conditioned by regenerative cells, and finally pancreatic islets are administered. In other embodiments devices are provided which allow for concurrent administration of pancreatic islets together with T cells and/or T regulatory cells that have been conditioned with regenerative cells. In another embodiment, the administration of T cells and/or T regulatory cells conditioned by regenerative cells is after administration of therapeutic pancreatic islets.

Abstract: Disclosed are means, compounds, and compositions of matter useful for stimulation of natural killer cell activity. On one embodiment a composition termed QuadraMune™ comprised of pterostilbene, Nigella sativa extract, green tea extract, and broccoli. In some embodiments the invention teaches the administration of a therapeutic combination of ingredients comprising of metformin, pterostilbene, Nigella sativa, sulforaphane, and epigallocatechin-3-gallate (EGCG) to a mammal in need of natural killer cell immune modulation. In another embodiment, the invention teaches administration of said therapeutic combination to a mammal infected with said SARS-CoV-2. In some embodiments dosage of said therapeutic combination is based on inflammatory and/or immunological parameters observed in patients with COVID-19.

Abstract: Disclosed are means, methods and compositions of matter useful for stimulation enhancement of T cell homing into tumors and overcoming tumor microenvironment. In one embodiment the invention provides an engineered T cell in which engagement of T cell receptor on said T cell results in upregulation of T cell attracting chemokines so as to induce an increased proportion of T cells to tumor cells. In another embodiment, T cell chemokine secreting cells are administrated intratumorally in order to augment T cell infiltration into said tumors. In other embodiments administration of lymphopoietic cytokines is performed intratumorally to enhance viability of T cells approaching and residing in the microenvironment. Combinations of agents which counteract tumor microenvironment induced immune suppression are also disclosed.

Abstract: Disclosed are aptamers designed to bind immunological checkpoint molecules while concurrently suppressing tumor associated gene expression through delivery of DNA molecules encoding short hairpin DNA. In one embodiment the invention provides an aptamer capable of binding PD-1 and/or PD-1 ligand while concurrently possessing ability to induce RNA interference to one more multiple other immune inhibitory and/or oncogenesis related genes. In one embodiment such a dual-targeting aptamer is utilized to induce systemic tumor abscopal effect.

Abstract: Disclosed are combination therapies for cancer utilizing the leverage of the adaptive immune system through chimeric antigen receptor (CAR) T cells, combined with leveraging the innate immune system by using CAR-macrophages (CAR-M) and CAR-natural killer (NK) cells. In some embodiments, the invention teaches the initial modification of the tumor microenvironment by administration of CAR-M and CAR-NK. The alteration of the tumor microenvironment results in reduction of barriers for CAR-T cells to enter the tumor, which allows for efficacy of CAR-T in treatment of solid tumors. In some embodiments adjuvant immunotherapies are utilized to expand immunological attack such as addition of complement, immunotherapeutic antibodies, chemotherapy and radiotherapy approaches.

Abstract: Disclosed are prophylactic and therapeutic approaches to Orthopox viral infections. In one embodiment the invention teaches utilization of regenerative cell conditioned media as a prophylactic/therapeutic agent. Synergies with antivirals and immunotherapies are further described. In one specific embodiment, mesenchymal stem cells are activated in vitro with trigger agents activating Toll-Like Receptors (TLRs), NOD-Like Receptors (NLRs), and RIG-I-Like Receptors (RLRs) and conditioned media is isolated and utilized as a therapeutic. Quantification of activity is performed by assessment of antiviral activity and/or ability to stimulate NK mediated cytolysis. Additionally, means of treating Orthopox viral infections (Smallpox, Monkeypox, etc.) by direct administration of stem cells and/or products thereof such as exosomes are disclosed.

Abstract: Disclosed are means, methods and compositions of matter useful for prevention of space flight associated bone density loss. In one embodiment, the invention provides cellular populations capable of suppressing osteoclast function and/or stimulating osteoblast activity. The use of mesenchymal stem cell populations alone, or more preferably, selected by expression of CD56 protein are disclosed. Cells may be administered systemically, or locally through the use of various matrices disclosed in this invention.

Abstract: Disclosed are means, methods and compositions of matter for prevention of hair loss and/or regeneration of hair follicles utilizing stem cell-based approaches and synergies with stimulating and/or hormone modulating agents. In one embodiment the invention discloses specific platelet rich plasma (PRP) combinations alone or with bone marrow stem cells to augment hair restoration and stimulate expansion of hair follicle associated T regulatory cell.

Abstract: Disclosed are means of treatment for age related or premature reproductive failure through concurrent administration of regenerative cells together with adjuvants capable of enhancing activity of said regenerative cells. In one embodiment, the invention provides administration of autologous bone marrow mononuclear cells in the endometrium and ovarian tissue. Administration of said type of regenerative cells is combined with anti-oxidants and/or regenerative adjuvants capable of reducing inflammation and/or fibrosis, as well as providing a suitable environment for optimal regenerative function of stem cells.

Abstract: Disclosed are methods, and compositions useful for stimulation of immunity towards cancer by utilizing dendritic cells and products therefrom that have been stimulated and/or incorporated mRNA encoding survivin and/or related gene sequences, defined herein as “survivin modified mRNA”. In one embodiment dendritic cells generated from allogeneic “off the shelf” sources are transfected with survivin modified mRNA and the cells are administered in an immunogenic manner. In some embodiments transfected dendritic cells are induced to undergo immunogenic cell death ex vivo subsequently to which they are used as immunogenic stimuli. In other embodiments preparation of the injection site is performed prior to administration of dendritic cells that have been transfected with survivin modified mRNA by pre-administration of agents increasing the number of local dendritic cells in the skin.

Abstract: Disclosed are methods, means, and compositions of matter useful for enhancing regenerative activity of bone marrow mononuclear cells/aspirate by coadministration with oxytocin. In one embodiment the invention teaches the treatment of peripheral artery disease by intramuscular administration of oxytoxin and bone marrow mononuclear cells/aspirate in proximity. The invention provides therapeutic doses, kits, and adjuvants useful in enhancing regenerative activity of bone marrow mononuclear cells/aspirate.

Abstract: Methods and compositions are provided to treat limb ischemia such as Beurger's Disease through the use of bone marrow stem cells that are administered prior to, concurrently with, and subsequently to administration of agents that modify the microenvironment of the ischemic limb(s). In one embodiment, said agents are antioxidants, more specifically antioxidants capable of diffusing across ischemic areas and preserving regenerative activity of administered stem cells. In another embodiment, the invention provides hormonal modifications to overcome deficiencies associated with ischemia predisposing pathologies.

Abstract: Described are means, methods, and compositions useful for treatment of multiple sclerosis through the utilization of fibroblasts and/or derivatives thereof to concurrently stimulate regenerative processes while inducing a protolerogenic immune modulatory program. In certain embodiments, fibroblasts are selected for the concurrent properties of immune modulation and regeneration by enrichment for CD73 expressing fibroblasts. In particular embodiments, stimulation of regeneration implies activation of endogenous neural progenitor cells. In some embodiments, stimulation of regeneration implies induction of remyelination. The utilization of fibroblasts as a superior source for immune modulation, prevention of immune mediated pathology, and activation of T regulatory cells is provided within the context of multiple sclerosis.

Abstract: Treatment of rheumatoid arthritis has been revolutionized by the introduction of TNF-alpha blockers, which represent a 40 billion dollar annual market. Unfortunately, a significant proportion of patients fail to respond to these treatments. The current invention provides the use of stem cell conditioned T cells to overcome resistance to TNF-alpha blockers by concurrently providing a source of immune modulatory and regenerative cells that synergize with TNF-alpha blockers.

Abstract: The invention provides means, methods and some compositions of matter useful to treat ovarian failure. In one embodiment progenitor cells possessing ability to differentiate along the monocytic and granulocyte linages are utilized as a source of cytokines for stimulation of ovarian repair/regeneration. Generation of said cells, such as classically termed myeloid derived suppressor cells is performed from sources including cord blood, bone marrow, mobilized peripheral blood and pluripotent stem cells. The invention further provides means of suppressing fibrosis and ongoing inflammation associated with ovarian dysfunction.

Abstract: Disclosed herein are methods and compositions for reducing inflammation in a subject. Aspects are directed to reduction of pulmonary inflammation using fibroblasts or fibroblast derived products. In some cases, fibroblasts or fibroblast-derived products are provided to a subject to reduce pulmonary inflammation, thereby treating or preventing airway allergy, asthma, or asthma-related symptoms. Embodiments encompass use of fibroblast-derived products, including exosomes, conditioned media, and other components derived from fibroblasts.

Abstract: In some aspects, disclosed are methods and compositions for disc regeneration and/or repair using one or more components from conditioned media from fibroblasts. In certain cases, conditioned media is obtained from fibroblasts stimulated with one or more opioid receptor antagonists and one or more toll-like receptor agonists. Conditioned media from fibroblasts may be provided in an effective amount to an individual in need thereof.

Abstract: Disclosed are novel cellular compositions of matter and treatment means for generation of universal donor regenerative T cells by exposure to mesenchymal stem cells or supernatant derived thereof. In one embodiment, regenerative T cells are created by differentiation of pluripotent stem cells in the presence of supernatant generated from activated mesenchymal stem cell population. The invention provides for creation of T cells which are capable of endowing regenerative activity, and/or anti-inflammatory, and/or angiogenic activity.

Abstract: Embodiments of the disclosure include methods and compositions for disc repair in a mammal using conditioned media (and/or one or more components therefrom) from fibroblasts that have been de-differentiated and cultured optionally with one or more particular conditions and/or compositions. In specific cases, fibroblasts that have been de-differentiated are exposed to hypoxia, histone deacetylase inhibitor(s), DNA methyltransferase inhibitor(s), or a combination thereof, and the conditioned media therefrom is provided in an effective amount to an individual.