Evidence of restorative therapies in the treatment of Peyronie disease: A narrative review.

OBJECTIVE: To describe the evidence of Platelet Rich Plasma (PRP), Stem cells therapy (SCT) and Extracorporeal shockwave therapy (ESWL) for the treatment of Peyronies disease (PD), including information from the main urological society guidelines. MATERIALS AND METHODS: A literature review of PubMed articles published between 2000 and 2023 was conducted, utilizing keywords such as "Peyronie's Disease", "Penile curvature", "Platelet Rich Plasma", "Stem cells", and "Extracorporeal shockwave therapy". Only full-text articles in English were included, excluding case reports and opinions. RESULTS: A considerable number of clinical trials were conducted using PRP penile injections for therapy of PD, showing reduction of curvature, plaque size and improvement in quality of life. Preclinical studies in rats have shown the potential benefit of adipose-derived stem cells, with improvements in erectile function and fibrosis. Human studies with mesenchymal stem cells demonstrated promising results, with reduction of curvature and plaque size. ESWL effects on PD were investigated in randomized clinical trials and demonstrated no significant impact in curvature or plaque size, but reasonable effect on pain control. CONCLUSION: Restorative therapies has emerged as an innovative treatment option for PD and the results from current studies appear to be promising and demonstrated good safety profile. Unfortunately, due to scarce evidence, PRP and SCT are still considered experimental by American Urological Association (AUA) and European Association of Urology (EAU) guidelines. ESWT is recommended, by the same guidelines, for pain control only. More high-quality studies with long-term follow-up outcomes are needed to evaluate efficacy and reproducibility of those therapies.

Advanced cell and gene therapies in cardiology.

We review the evidence for the presence of stem/progenitor cells in the heart and the preclinical and clinical data using diverse cell types for the therapy of cardiac diseases. We highlight the failure of adult stem/progenitor cells to ameliorate heart function in most cardiac diseases, with the possible exception of refractory angina. The use of pluripotent stem cell-derived cardiomyocytes is analysed as a viable alternative therapeutic option but still needs further research at preclinical and clinical stages. We also discuss the use of direct reprogramming of cardiac fibroblasts into cardiomyocytes and the use of extracellular vesicles as therapeutic agents in ischemic and non-ischemic cardiac diseases. Finally, gene therapies and genome editing for the treatment of hereditary cardiac diseases, ablation of genes responsible for atherosclerotic disease, or modulation of gene expression in the heart are discussed.

Lung Progenitor and Stem Cell Transplantation as a Potential Regenerative Therapy for Lung Diseases.

Chronic lung diseases are debilitating illnesses ranking among the top causes of death globally. Currently, clinically available therapeutic options capable of curing chronic lung diseases are limited to lung transplantation, which is hindered by donor organ shortage. This highlights the urgent need for alternative strategies to repair damaged lung tissues. Stem cell transplantation has emerged as a promising avenue for regenerative treatment of the lung, which involves delivery of healthy lung epithelial progenitor cells that subsequently engraft in the injured tissue and further differentiate to reconstitute the functional respiratory epithelium. These transplanted progenitor cells possess the remarkable ability to self-renew, thereby offering the potential for sustained long-term treatment effects. Notably, the transplantation of basal cells, the airway stem cells, holds the promise for rehabilitating airway injuries resulting from environmental factors or genetic conditions such as cystic fibrosis. Similarly, for diseases affecting the alveoli, alveolar type II cells have garnered interest as a viable alveolar stem cell source for restoring the lung parenchyma from genetic or environmentally induced dysfunctions. Expanding upon these advancements, the use of induced pluripotent stem cells to derive lung progenitor cells for transplantation offers advantages such as scalability and patient specificity. In this review, we comprehensively explore the progress made in lung stem cell transplantation, providing insights into the current state of the field and its future prospects.

New Perspectives in Stem Cell Transplantation and Associated Therapies to Treat Retinal Diseases: From Gene Editing to 3D Bioprinting.

Inherited and non-inherited retinopathies can affect distinct cell types, leading to progressive cell death and visual loss. In the last years, new approaches have indicated exciting opportunities to treat retinopathies. Cell therapy in retinitis pigmentosa, age-related macular disease, and glaucoma have yielded encouraging results in rodents and humans. The first two diseases mainly impact the photoreceptors and the retinal pigmented epithelium, while glaucoma primarily affects the ganglion cell layer. Induced pluripotent stem cells and multipotent stem cells can be differentiated in vitro to obtain specific cell types for use in transplant as well as to assess the impact of candidate molecules aimed at treating retinal degeneration. Moreover, stem cell therapy is presented in combination with newly developed methods, such as gene editing, Müller cells dedifferentiation, sheet & drug delivery, virus-like particles, optogenetics, and 3D bioprinting. This review describes the recent advances in this field, by presenting an updated panel based on cell transplants and related therapies to treat retinopathies.

Stem cell therapy for erectile dysfunction: a systematic review.

INTRODUCTION: Erectile dysfunction (ED) is a common condition that negatively affects men's quality of life. It can have various causes, including psychological, vascular, and neurologic factors. Existing treatments for ED mainly focus on symptom relief rather than addressing the underlying cause. Stem cells (SCs) have shown potential as a therapeutic approach for ED due to their anti-inflammatory properties. OBJECTIVES: This systematic review aims to assess the current status of trials and determine the potential impact of SCs on male sexual health. METHODS: A comprehensive search strategy was employed to gather relevant articles from 6 electronic databases. The search included articles published until March 2023. The reference lists of articles were manually reviewed to identify additional studies of relevance. The eligibility criteria for inclusion in the analysis focused on clinical trials involving humans that evaluated the safety and efficacy of SC therapy for ED. Exclusion criteria encompassed case reports, case series, abstracts, reviews, and editorials, as well as studies involving animals or SC derivatives. Data extraction was performed via a standardized form with a focus on erectile outcomes. RESULTS: A total of 2847 articles were initially identified; 18 were included in the final analysis. These studies involved 373 patients with ED and various underlying medical conditions. Multiple types of SC were utilized in the treatment of ED: mesenchymal SCs, placental matrix-derived mesenchymal SCs, mesenchymal SC-derived exosomes, adipose-derived SCs, bone marrow-derived mononuclear SCs, and umbilical cord blood SCs. CONCLUSION: SC therapy shows promise as an innovative and safe treatment for organic ED. However, the lack of standardized techniques and controlled groups in many studies hampers the ability to evaluate and compare trials.

Relapsed ALL: CAR T vs transplant vs novel therapies.

Chimeric antigen receptor T-cell therapy targeting CD19 (CART19) has expanded the treatment options for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). The approval of tisagenlecleucel for pediatric and young adult patients with r/r ALL has allowed broader access for some patients, but the treatment of older adults is available (at the time of this writing) only within a clinical trial. High remission rates have been consistently observed with varied CART19 products and treatment platforms, but durability of remissions and thus the potential role of a consolidative allogeneic stem cell transplant (SCT) is more uncertain and likely to vary by product and population treated. The immunologic characteristics of CARTs that confer high response rates also account for the life-threatening toxicities of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, the severity of which also varies by patient and disease characteristics and product. Further considerations informing a decision to treat include feasibility of leukapheresis and timeline of manufacture, alternative treatment options available, and the appropriateness of a potential consolidative allogeneic SCT. Advances in the field are under way to improve rate and duration of responses and to mitigate toxicity.

Functional Recovery Caused by Human Adipose Tissue Mesenchymal Stem Cell-Derived Extracellular Vesicles Administered 24 h after Stroke in Rats.

Ischemic stroke is a major cause of death and disability, intensely demanding innovative and accessible therapeutic strategies. Approaches presenting a prolonged period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. Here, we evaluated the potential neuroprotective properties of nasally administered human adipose tissue mesenchymal stem cell (hAT-MSC)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. After a single intranasal EV (200 µg/kg) administered 24 h after a focal permanent ischemic stroke in rats, a higher number of EVs, improvement of the blood-brain barrier, and re-stabilization of vascularization were observed in the recoverable peri-infarct zone, as well as a significant decrease in infarct volume. In addition, EV treatment recovered long-term motor (front paws symmetry) and behavioral impairment (short- and long-term memory and anxiety-like behavior) induced by ischemic stroke. In line with these findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

Stem Cells as a Model of Study of SARS-CoV-2 and COVID-19: A Systematic Review of the Literature.

BACKGROUND: The SARS-CoV-2 virus is the cause of the latest pandemic of the 21st century; it is responsible for the development of COVID-19. Within the multiple study models for both the biology and the treatment of SARS-CoV-2, the use of stem cells has been proposed because of their ability to increase the immune response and to repair tissue. Therefore, the objective of this review is to evaluate the role of stem cells against SARS-CoV-2 and COVID-19 in order to identify their potential as a study model and as a possible therapeutic source against tissue damage caused by this virus. Therefore, the following research question was established: What is the role of stem cells in the study of SARS-CoV-2 and the treatment of COVID-19? MATERIALS AND METHODS: A search was carried out in the electronic databases of PUBMED, Scopus, and ScienceDirect. The following keywords were used: "SARS-CoV-2," "COVID-19," and "STEM CELL," plus independent search strategies with the Boolean operators "OR" and "AND." The identified reports were those whose main objective was the study of stem cells in relation to SARS-CoV-2 or COVID-19. For the development of this study, the following inclusion criteria were taken into account: studies whose main objective was the study of stem cells in relation to SARS-CoV-2 or COVID-19 and clinical case studies, case reports, clinical trials, pilot studies, in vitro, or in vivo studies. For assessment of the risk of bias for in vitro studies, the SciRAP tool was used. The data collected for each type of study, clinical or in vitro, were analyzed with descriptive statistics using the SPSS V.22 program. RESULTS: Of the total of studies included (n = 39), 22 corresponded to in vitro investigations and 17 to human studies (clinical cases (n = 9), case series (n = 2), pilot clinical trials (n = 5), clinical trials (n = 1)). In vitro studies that induced pluripotent stem cells were the most used (n = 12), and in clinical studies, the umbilical stem cells derived were the most reported (n = 11). The mean age of the study subjects was 58.3 years. After the application of stem cell therapy, the follow-up period was 8 days minimum and 90 days maximum. Discussion. The mechanism by which the virus enters the cell is through protein "S," located on the surface of the membrane, by recognizing the ACE2 receptor located on the target cell. The evidence that the expression of ACE2 and TMPRSS2 in stem cells indicates that stem cells from bone marrow and amniotic fluid have very little expression. This shows that stem cell has a low risk of infection with SARS-CoV-2. CONCLUSION: The use of stem cells is a highly relevant therapeutic option. It has been shown in both in vitro studies and clinical trials that it counteracts the excessive secretion of cytokines. There are even more studies that focus on long-term follow-up; thus, the potential for major side effects can be analyzed more clearly. Finally, the ethical use of stem cells from fetal or infant origin needs to be regulated. The study was registered in PROSPERO (no. CRD42021229038). The limitations of the study were because of the methodology employed, the sample was not very large, and the follow-up period of the clinical studies was relatively short.

Eficacia de la movilización de células madre en pacientes con Polineuropatía Desmielinizante Inflamatoria Crónica refractaria / Efficacy of mobilization of stem cells in patients with Refractory Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Introducción: La polineuropatía desmielinizante inflamatoria crónica (CIDP) es una enfermedad desmielinizante e inflamatoria de mediación autoinmune. El tratamiento convencional es basado en la inmunomodulación e inmunosupresión. El uso de células madre es una terapia novedosa en los trastornos autoinmune, siendo incluida como terapia. Objetivo: Determinar la eficacia de la movilización de células madre mediante la aplicación del factor estimulador de colonias granulocíticas (F-ECG) en pacientes con CIDP que han recibido otras líneas de tratamiento. Material y Métodos: Se realizó un estudio aleatorizado, doble ciego sobre una cohorte de 45 pacientes con CIDP, donde se administró el (F-ECG) en 25 pacientes y 20 continuaron con el tratamiento habitual, tratados anteriormente con otras variantes terapéuticas por más de tres años, sin respuesta satisfactoria. Resultados: Predominio de los hombres para 64,4 por ciento, la Diabetes Mellitus tuvo mayor asociación y la medicación más usada fueron los esteroides. Los síntomas y signos clínicos mejoraron significativamente tras el tratamiento. Los valores de la puntuación del TCSS al mes y 3 meses después del tratamiento disminuyeron significativamente; pero este decremento no se mantuvo al final del estudio. La velocidad de conducción y el potencial de acción de los nervios sensoriales y motores mejoraron considerablemente después del tratamiento. Conclusiones: La efectividad de la aplicación del (F-ECG) para la mejoría de los síntomas clínicos y resultados de estudios neurofisiológicos evolutivamente son mayores que otras variantes terapéuticas en los primeros meses, con buena seguridad y tolerabilidad, por lo que se puede incluir en la terapéutica convencional para la CIDP(AU)

Introduction: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune demyelinating disease. Conventional treatment is based on immunomodulation and immunosuppression. The use of stem cells is a novel therapy in autoimmune disorders, so it is included as therapy. Objective: To determine the efficacy of mobilization of stem cells by applying granulocyte colony-stimulating factor (G-CSF) in patients with CIDP who have followed other lines of treatment. Material and Methods: A randomized, double-blind study was carried out on a cohort of 45 patients with CIDP. G-CSF was administered to 25 patients and 20 of them continued with the usual treatment. These patients were previously treated with other therapeutic variants for more than three years without satisfactory response. Results: There was a prevalence of men (64.4 percent), Diabetes Mellitus had a greater association, and the most used medications were steroids. Clinical symptoms and signs improved significantly after treatment. TCSS scores significantly decreased at one and three months after treatment, but this decrease was not maintained at the end of the study. The conduction velocity and action potential of sensory and motor nerves improved considerably after treatment. Conclusions: The effectiveness of the use of G-CSF shows an improvement of clinical symptoms. The results of neurophysiological studies have a better course than other therapeutic variants during the first months, with good safety and tolerability, so it can be included in the conventional therapy for the CIDP(AU)

Preliminary study on testicular germ cell isolation and transplantation in an endangered endemic species Brycon orbignyanus (Characiformes: Characidae).

We aimed to develop a simplified protocol for transplantation of Brycon orbignyanus spermatogonial stem cells (SSCs) into Astyanax altiparanae testes. Brycon orbignyanus testes were enzymatically digested and SSC purified by a discontinuous density gradient. Endogenous spermatogenesis was suppressed in A. altiparanae using busulfan or by incubation at 35 °C water, and SSCs from B. orbignyanus labeled with PKH26 were injected into their testes via the urogenital papilla. Twenty-two hours post-transplantation, labeled spermatogonia were observed in A. altiparanae tubular lumen. After 7 days, spermatogonia proliferated in the epithelium, and 21 days post-transplantation, sperm was observed in the lumen. Of surviving host fish, nearly 67% of those treated with busulfan and 85% of those held in warm water showed labeled cells in host germinal epithelium. The present study standardized, by a simple and accessible method, germ cell transplantation between sexually mature Characiformes fish species. This is the first report of xenogenic SSC transplantation in this fish order.

Microcurrent and adipose-derived stem cells modulate genes expression involved in the structural recovery of transected tendon of rats.

Tendon injuries are common and have a high incidence of re-rupture that can cause loss of functionality. Therapies with adipose-derived stem cells (ASC) and the microcurrent (low-intensity electrical stimulation) application present promising effects on the tissue repair. We analyzed the expression of genes and the participation of some molecules potentially involved in the structural recovery of the Achilles tendon of rats, in response to the application of both therapies, isolated and combined. The tendons were distributed in five groups: normal (N), transected (T), transected and ASC (C) or microcurrent (M) or with ASC, and microcurrent (MC). Microcurrent therapy was beneficial for tendon repair, as it was observed a statistically significant increase in the organization of the collagen fibers, with involvement of the TNC, CTGF, FN, FMDO, and COL3A1 genes as well as PCNA, IL-10, and TNF-α. ASC therapy significantly increased the TNC and FMDO genes expression with no changes in the molecular organization of collagen. With the association of therapies, a significant greater collagen fibers organization was observed with involvement of the FMOD gene. The therapies did not affect the expression of COL1A1, SMAD2, SMAD3, MKX, and EGR1 genes, nor did they influence the amount of collagen I and III, caspase-3, tenomodulin (Tnmd), and hydroxyproline. In conclusion, the application of the microcurrent isolated or associated with ASC increased the organization of the collagen fibers, which can result in a greater biomechanical resistance in relation to the tendons treated only with ASC. Future studies will be needed to demonstrate the biological effects of these therapies on the functional recovery of injured tendons.

Early Expression of Neuronal Dopaminergic Markers in a Parkinson's Disease Model in Rats Implanted with Enteric Stem Cells (ENSCs).

BACKGROUND: Parkinson's Disease (PD) is a common neurodegenerative disorder affecting the dopaminergic (DAergic) system. Replacement therapy is a promising alternative aimed at reconstructing the cytoarchitecture of affected brain regions in PD. Experimental approaches, such as the replacement of DAergic neurons with cells obtained from the Enteric Nervous System (ENS) has yet to be explored. OBJECTIVE: To establish and characterize a cell replacement strategy with ENS Cells (ENSCs) in a PD model in rats. METHODS: Since ENSCs can develop mature DAergic phenotypes, here we cultured undifferentiated cells from the myenteric plexus of newborn rats, establishing that they exhibit multipotential characteristics. These cells were characterized and further implanted in the Substantia nigra pars compacta (SNpc) of adult rats previously lesioned by a retrograde degenerative model produced by intrastriatal injection of 6-Hydroxydopamine (6-OHDA). DAergic markers were assessed in implants to validate their viability and possible differentiation once implanted. RESULTS: Cell cultures were viable, exhibited stem cell features and remained partially undifferentiated until the time of implant. The retrograde lesion induced by 6-OHDA produced DAergic denervation, reducing the number of fibers and cells in the SNpc. Implantation of ENSCs in the SNpc of 6-OHDAlesioned rats was tracked after 5 and 10 days post-implant. During that time, the implant increased selective neuronal and DAergic markers, Including Microtubule-Associated Protein 2 (MAP-2), Dopamine Transporter (DAT), and Tyrosine Hydroxylase (TH). CONCLUSION: Our novel results suggest that ENSCs possess a differentiating, proliferative and restorative potential that may offer therapeutic modalities to attenuate neurodegenerative events with the inherent demise of DAergic neurons.

Clinical studies using stem cells for treatment of retinal diseases: state of the art / Estudos clínicos com uso de células-tronco para tratamento de doenças da retina: estado da arte

ABSTRACT Degenerative retinal diseases such as retinitis pigmentosa, Stargardt's macular dystrophy, and age-related macular degeneration are characterized by irreversible loss of vision due to direct or indirect photoreceptor damage. No effective treatments exist, but stem cell studies have shown promising results. Our aim with this review was to describe the types of stem cells that are under study, their effects, and the main clinical trials involving them.

RESUMO As doenças degenerativas da retina, como retinose pigmentar, distrofia macular de Stargardt e degeneração macular relaciona à idade, são caracterizadas por perda irre versível da visão devido a danos diretos ou indiretos aos fotorreceptores. Não existem tratamentos eficazes, porém os estudos com células-tronco mostraram resultados promissores. Nosso objetivo com esta revisão foi descrever os tipos de células-tronco em estudo, seus efeitos e os principais ensaios clínicos que as envolvem.

Clinical studies using stem cells for treatment of retinal diseases: state of the art.

Degenerative retinal diseases such as retinitis pigmentosa, Stargardt's macular dystrophy, and age-related macular degeneration are characterized by irreversible loss of vision due to direct or indirect photoreceptor damage. No effective treatments exist, but stem cell studies have shown promising results. Our aim with this review was to describe the types of stem cells that are under study, their effects, and the main clinical trials involving them.

Cell therapy for Parkinson's disease is coming of age: current challenges and future prospects with a focus on immunomodulation.

Parkinson's disease (PD) is a neurodegenerative disease that affects more than 1% of people over the age of 60. The principal feature of this disease is the progressive loss of dopaminergic neurons (DAn) within the nigrostriatal system, causing the motor symptoms observed in these patients. At present, there is no therapeutic approach with a cytoprotective effect that can prevent DAn cell death or disease progression. Cell replacement therapy began 30 years ago with the objective to compensate for the loss of DAn by transplantation of dopamine-producing cells. The results from these trials have provided proof of concept of safety and efficacy of cell replacement. However, a major limiting factor of this strategy has been the poor survival rate of grafted DAn. An important factor that could cause cell death of DA precursors is the host response to the graft. In this review, we discuss the factors that affect the outcome of cell therapy in PD, with focus on the cell types used and the functional effects of the host immune response on graft survival and differentiation. We also discuss the strategies that may increase the efficacy of cell replacement therapy which target the host immune response.

A Promising Future for Stem-Cell-Based Therapies in Muscular Dystrophies-In Vitro and In Vivo Treatments to Boost Cellular Engraftment.

Muscular dystrophies (MD) are a group of genetic diseases that lead to skeletal muscle wasting and may affect many organs (multisystem). Unfortunately, no curative therapies are available at present for MD patients, and current treatments mainly address the symptoms. Thus, stem-cell-based therapies may present hope for improvement of life quality and expectancy. Different stem cell types lead to skeletal muscle regeneration and they have potential to be used for cellular therapies, although with several limitations. In this review, we propose a combination of genetic, biochemical, and cell culture treatments to correct pathogenic genetic alterations and to increase proliferation, dispersion, fusion, and differentiation into new or hybrid myotubes. These boosted stem cells can also be injected into pretreate recipient muscles to improve engraftment. We believe that this combination of treatments targeting the limitations of stem-cell-based therapies may result in safer and more efficient therapies for MD patients. Matricryptins have also discussed.