Abstract: In some aspects, disclosed herein are methods and compositions for treatment of erectile dysfunction using regenerative fibroblasts or cells derived from fibroblasts. Methods and compositions disclosed also include those for generating regenerative fibroblast cells from fibroblasts. Also disclosed are methods and compositions for treatment of erectile dysfunction using regenerative fibroblast-conditioned media. Regenerative fibroblast cells generated from fibroblasts and regenerative fibroblast-conditioned media are also described.

Abstract: Disclosed herein are methods and compositions for treating or preventing ovarian failure using fibroblasts or cells derived from fibroblasts. In some embodiments, ovarian failure is pathological, the result of an intervention, or the result of aging. In some embodiments, regenerative fibroblast cells are administered locally into the ovary or pen-ovary areas or systemically. In some embodiments, regenerative cells act to suppress fibrosis of the ovaries, inhibit inflammation, stimulate maturation of immature ovarian progenitor cells, or directly differentiate into oocytes. In some embodiments, regenerative fibroblasts produce factors that inhibit apoptosis of oocytes and/or oocyte progenitors.

Abstract: Disclosed are treatments, compositions of matter, and protocols for reducing, ameliorating, or reversing excess inflammation and/or cytokine storm through administration of Sphagnum and/or extracts thereof. In particular embodiments, a patient at risk for cytokine storm is administered a Sphagnum extract at a concentration sufficient to induce an immunomodulatory change in said patient, including suppression of macrophage activation, reduction of neutrophil activation and inhibition of DNA extracellular trap release. In some embodiments, Sphagnum, or extracts thereof are administered together with other agents to enhance activity in treatment of Covid-19 infection and associated pathologies. In some embodiments, humic acid and/or analogues thereof are administered for reduction of pathological inflammation and/or stimulation of immunity.

Abstract: Embodiments of the disclosure include methods and compositions related to prevention of spontaneous miscarriage in an individual. In certain cases, fibroblasts are provided in an effective amount to an individual in need thereof. Alternatively or in addition, lymphocytes are obtained, cultured with fibroblasts, and provided to an individual. Fibroblasts may modulate an immune response in an individual, thereby reducing the risk of spontaneous miscarriage.

Abstract: Disclosed are means of enhancing therapeutic activities of fibroblasts through manipulation of nuclear receptor activation accomplished by, intra alia, alteration in hormone levels. In some embodiments angiogenic, and/or neurogenic, and/or immunomodulatory activities of fibroblasts are increased by normalization or augmentation of sex-specific hormones. In one embodiment a candidate for fibroblast therapy is administered hormones, pro-hormones, or growth factors to augment therapeutic activities of fibroblasts. In some embodiments fibroblasts are treated in vitro prior to administration with various hormones and/or growth factors in order to augment therapeutic activities of said cells.

Abstract: Disclosed are means, methods and compositions of matter useful for suppressing pathological production of new blood vessels in conditions such as cancer and wet macular degeneration. In one embodiment the invention provides silencing of NR2F6 using nucleic acid based approaches such as RNA interference, antisense oligonucleotides, or DICER. In another embodiment, the invention teaches the administration of small molecule NR2F6 inhibitors as means of selectively inhibiting pathological but not healthy angiogenesis.

Abstract: Aspects of the present disclosure are directed to methods and compositions for inducing the generation of cells capable of killing cancer associated fibroblasts at least in part through the generation of ex vivo expanded cord blood cells which are programmed to kill cancer associated fibroblasts. Certain aspects relate to generation of immune cells, including T cell and Natural Killer (NK) cells, for use in targeting cancer cells and cancer associated fibroblasts. Further aspects are directed to gene editing and/or gene silencing of immune checkpoint proteins in therapeutic immune cells.

Abstract: Disclosed are means, methods and compositions of matter for treatment of Graves’ Disease using non-modified and/or modified fibroblasts for promotion of immunological tolerance, and/or stimulation of antigen-specific tolerance. In some embodiments, fibroblasts are administered together with antigens associated with Graves’ Disease such as the thyrotropin receptor protein and/or peptides and/or altered peptide ligands derived thereof. In some embodiments, co-administration refers to administration simultaneously or within temporal proximity of each other. In some embodiments, co-administration refers to loading of fibroblasts with antigens and/ or epitopes of antigens associated with Graves’ Disease.

Abstract: The disclosure provides means of treating autoimmunity through reprogramming of antigen presenting cells in an individual in need of treatment through administration of fibroblasts and/or derivatives of fibroblasts. In one embodiment, fibroblasts are administered in an allogeneic manner subsequent to modification which endows fibroblast ability to alter antigen presenting cells in a manner which supports the generation of immunological tolerance as opposed to immunological rejection. In one embodiment, fibroblasts are utilized to decrease costimulatory molecule expression on antigen presenting cells, in order to allow for production of antigen-specific immunological tolerance promoting cells.

Abstract: Embodiments of the disclosure encompass methods and compositions related to treatment of Acute Respiratory Distress Syndrome caused by any reason, including caused by a coronavirus, for example. In particular embodiments, fibroblasts are delivered to an individual in need thereof to stimulate generation of T regulatory cells that may or may not be FoxP3-positive, and/or immune regulatory cells previously exposed to fibroblasts are delivered to the individual.

Abstract: Disclosed are T regulatory cells endogenously occurring or generated in vitro which possess regenerative activity. In one embodiment said T regulatory cells are created by culture with derivatives of activated/enhanced mesenchymal stem cells. Said derivatives include apoptotic bodies, conditioned media, exosomes, microvesicles, proteins and various metabolites. In one embodiment said mesenchymal stem cells are activated with cytokines such as interferon gamma. In other embodiments are said mesenchymal stem cells are activated by ligation of toll like receptors. Cells of the invention are useful for treatment of autoimmune, degenerative, and combination of autoimmune and degenerative disease. Other uses of said regenerative T cells include treatment of heart failure, liver failure, stroke, and ischemic diseases.

Abstract: Embodiments of the disclosure concern methods and compositions of treating or preventing viral infection, including of SARS-CoV-2, for example. In specific embodiments, one or more adjuvants are delivered to an individual receiving and/or having received fibroblasts and/or fibroblast-derived exosomes. In specific cases, the adjuvants comprise particular peptides, chloroquine and/or hydroxychloroquine, and/or one or more activators of one or more toll like receptors.

Abstract: Disclosed are means, methods, and compositions of matter useful for treatment of autoimmunity comprising exposing patient T cells fibroblasts possessing tolerogenic properties. In one embodiment peripheral blood mononuclear cells are cultured in the presence of CD73 selected fibroblasts alone or in the presence of interleukin-2, and/or IL-7, and/or TGF-beta, and/or PGE-2 for a period of time sufficient to endow tolerogenic properties. Said tolerogenic properties include ability to suppress adaptive or innate immune responses. In another embodiment the disclosure provides methods of generating antigen specific immune regulatory cells by culture of T cells together with fibroblasts in the presence of antigen to which specific immune regulation is desired.

Abstract: In some aspects, disclosed herein are methods and compositions for treatment or prevention of cerebral palsy using fibroblasts or derivatives thereof. Disclosed herein are fibroblasts and derivatives thereof capable of inducing neurogenesis and/or reducing inflammation in a subject. In some cases, the disclosed methods comprise use of conditioned fibroblasts. Fibroblasts may be conditioned with agents capable of enhancing therapeutic efficacy, for example oxytocin and/or human chorionic gonadotrophin (hCG).

Abstract: Disclosed herein are methods and compositions for modulation of telomere length in cells. Aspects are directed to reduction in telomere shortening rate, stabilization of telomere shortening, and/or telomere elongation using fibroblasts or fibroblast-derived products. In some cases, provided are methods for treatment of telomere-associated conditions using fibroblasts or fibroblast-derived products. Fibroblasts may be provided to modulate telomere length in cells of a subject, thereby treating a telomere-associated condition such as, for example, cancer, aging, or idiopathic pulmonary fibrosis.

Abstract: Disclosed are means of suppressing production of the inflammatory cytokine TNF-alpha through contact-dependent and contact-independent means by fibroblast populations and products and/or derivatives of fibroblast populations. In one embodiment, fibroblasts are cultured under conditions allowing proliferation of said fibroblasts, wherein said proliferative status of fibroblasts correlates with the ability to directly suppress TNF-alpha production, and/or to release one or more factors capable of suppressing TNF-alpha production. In one embodiment, fibroblasts are used for treatment of inflammatory diseases by their ability to suppress TNF-alpha production. In other embodiments, conditioned media and/or exosomes of said fibroblasts are utilized to treat inflammatory diseases by their ability to suppress TNF-alpha production.

Abstract: Embodiments of the disclosure concern reducing deleterious effects of inflammatory cytokines, such as interleukin-17, by providing to an individual with inflammation or at risk for inflammation an effective amount of fibroblasts and/or fibroblast derivatives thereof that reduce production of IL-17 from immune cells, that suppress responsiveness of cells to IL17, and/or that suppress generation of Th17 cells.

Abstract: Disclosed are novel cellular populations generated by explosion of monocytic cells to conditioned media of regenerative cells. In one embodiment said regenerative cells are umbilical cord endothelial cells and said cells are pre-activated to possess enhance ability to reprogram said monocytic lineage cells. In one embodiment monocyte lineage cells are collected from leukopaks by plastic adherence and subsequently cultured in a manner to generate cells similar to M2 cells. In one embodiment said monocytic cells are cultured in a manner to generate myeloid derived suppressor cells. In one embodiment cells are generated to reducing inflammatory conditions. In another embodiment cells are generated for treatment of degenerative conditions. In another embodiment cells are generated for treatment of fibrosis.

Abstract: Embodiments of the disclosure include methods and compositions useful for treating cancer in an immunogenic manner so as to elicit local tumor regression, while priming systemic immunity. In one embodiment, there is expansion of tumor-specific immune cells through administration of fibroblasts, either natural or modified in an intratumoral and/or peritumoral manner. In other embodiments, manipulation of a local tumor microenvironment is achieved by injections of immune-modulating fibroblasts to facilitate expansion of immune effector cells, which are subsequently re-stimulated in the periphery by antigenic exposure. In another embodiment, agents are provided that allow for systemic derepression of immunity, while optionally augmenting ability of immune effector cells to expand and kill tumor cells.

Abstract: Disclosed is the utilization of cannabidiol, either through systemic and/or local administration, for use as an adjuvant in treatments of disc degenerative disease. In some embodiments, cannabidiol is utilized to enhance therapeutic and/or regenerative activities of fibroblasts. In other embodiments, cannabidiol is utilized to augment reparative effects of other regenerative cells including monocytes, mesenchymal stem cells, and/or hematopoietic stem cells. In some embodiments cannabidiol is utilized in the culture media of regenerative cells prior to administration of said cells.