Stem Cell Regenerative Medicine Research Articles

New avenues in the treatment of ischemic heart disease - Stem cell therapy

Faced with the large number of patients with ischemic heart disease and high mortality rates, traditional drug treatments come with the risks of drug resistance and rebound effects after discontinuation, as well as the shortcomings of surgical treatments such as poor blood circulation and the inability to restore necrotic myocardium. This article starts from the perspective of stem cell regenerative medicine, focusing on the stem cell therapy for ischemic heart disease, and provides a comprehensive review of the types of stem cells and transplantation methods. It also includes further summaries and prospects, believing that more comprehensive and improved treatment methods will emerge in the future to benefit patients.

Adipose tissue: A treasure trove of stem cells for regenerative medicine

Adipose tissue: A treasure trove of stem cells for regenerative medicine Adipose tissue, commonly known as fat, has long been considered a mere energy reservoir. However, recent discoveries have revolutionized our understanding of this tissue, placing it at the heart of advances in stem cells and regenerative medicine. To shed light on these questions, we will rely on the expertise of Doctors Saja Scherer and Giorgio Pietramaggiori from the Global Medical Institute clinic in Lausanne. These two eminent specialists are at the forefront of research and clinical applications of adipose tissue in regenerative medicine. Dr. Saja Scherer, a renowned plastic surgeon, is recognized for her innovative work on the use of adipose tissue in facial reconstruction and rejuvenation. Her research has contributed to improving fat grafting techniques, thus optimizing results for patients.

3D printing incorporating gold nanozymes with mesenchymal stem cell-derived hepatic spheroids for acute liver failure treatment

Acute liver failure (ALF) is a highly fatal disease, necessitating the advancement and optimization of alternative therapeutic strategies to benefit patients awaiting liver transplantation. In this study, we innovatively established the antioxidant nanozyme-hepatocyte-like cells (HLCs) microtissue sheets (HS/N–Au@composite) for ALF therapy. We first prepared a 3D-printed hyaluronic acid/gelatin/sodium alginate scaffold with N-acetylcysteine (NAC)-capped gold nanoclusters (NAC-Au NCs), forming the N–Au@hydrogel. For the encapsulation of HLC spheroids, we used a biocompatible hybrid hydrogel composed of decellularized extracellular matrix (dECM), thrombin, and fibrinogen, resulting in the HS@dECM hydrogel. Utilizing 3D printing technology, we integrated the N–Au@hydrogel with the HS@dECM hydrogel to create the HS/N–Au@composite for in situ transplantation to treat ALF. Our results demonstrated that NAC-Au NCs effectively mitigated reactive oxygen species (ROS)-induced liver necrosis in ALF. Additionally, the N–Au@hydrogel provided mechanical support, ensuring the proper landing and effective functioning of the transplanted HLC spheroids. The HS/N–Au@composite synergistically decreased serum transaminase levels, reduced the accumulation of pro-inflammatory cytokines, accelerated liver function recovery, and promoted liver regeneration in ALF treatment. This combination of HLC spheroids and NAC-Au NCs nanozymes via 3D-printed composite scaffolds represents a promising strategy for enhancing hepatocyte transplantation and advancing stem cell regenerative medicine in ALF therapy.

Abstract We028: Decoding m6a RNA methylomes identifies Igf2bp1 as a common barrier to direct reprogramming

Direct reprogramming has revolutionized the fields of stem cell biology and regenerative medicine. Targeted transdifferentiation of cells in situ holds significant promise in treating a large swathe of illness and injury including cardiovascular disease. However, much remains unknown about the molecular mechanisms of direct reprogramming, particularly its post-transcriptional regulation, including the role of m6a RNA modification. Here, by characterizing early changes in the m6a RNA methylome during reprogramming of fibroblasts toward three distinct lineages—cardiac, hepatic and neuronal—we identify lineage-specific features as well as common regulatory patterns. Our data reveal extensive changes in m6a methylome of direct reprogramming with clear impacts on cell fate decisions. Through loss-of-function screening of m6a readers, we uncovered Igf2bp1(insulin-like growth factor 2 mRNA binding protein 1) as a shared barrier to direct reprogramming. Further mechanistic studies will show how Igf2bp1 influences the reprogramming process mediated via m6a modifications. Collectively, our results present a fascinating portrait of m6a RNA methylome during direct reprogramming and reveal a key role of Igf2bp1 in maintaining cell fate, enhancing our mechanistic understanding of the reprogramming process.

Radiation-Induced Cognitive Decline: Challenges and Solutions.

Radiation therapy, a common treatment for central nervous system cancers, can negatively impact cognitive function, resulting in radiation-induced cognitive decline (RICD). RICD involves a decline in cognitive abilities such as memory and attention, likely due to damage to brain white matter, inflammation, and oxidative stress. The multifactorial nature of RICD poses challenges including different mechanisms of injury (neurogenesis, oxidative stress and neuroinflammation, dendritic structure alterations and vascular effects) and confounding factors like advanced age, and pre-existing conditions. Despite these challenges, several potential solutions exist. Neuroprotective agents like antioxidants can mitigate radiation damage, while cognitive rehabilitation techniques such as cognitive training and memory strategies improve cognitive function. Advanced imaging techniques like magnetic resonance imaging (MRI) help identify vulnerable brain areas, and proton therapy offers precise targeting of cancer cells, sparing healthy tissue. Multidisciplinary care teams are crucial for managing RICD's cognitive and psychological effects. Personalized medicine, using genetic and molecular data, can identify high-risk patients and tailor treatments accordingly. Emerging therapies, including stem cell therapy and regenerative medicine, offer hope for repairing or replacing damaged brain tissue. Addressing RICD is vital for cancer survivors, necessitating consideration of cognitive function and provision of appropriate support and resources for those experiencing cognitive decline.

In Vitro Biocompatibility Assessment of Bioengineered PLA-Hydrogel Core-Shell Scaffolds with Mesenchymal Stromal Cells for Bone Regeneration.

Human mesenchymal stromal cells (hMSCs), whether used alone or together with three-dimensional scaffolds, are the best-studied postnatal stem cells in regenerative medicine. In this study, innovative composite scaffolds consisting of a core-shell architecture were seeded with bone-marrow-derived hMSCs (BM-hMSCs) and tested for their biocompatibility and remarkable capacity to promote and support bone regeneration and mineralization. The scaffolds were prepared by grafting three different amounts of gelatin-chitosan (CH) hydrogel into a 3D-printed polylactic acid (PLA) core (PLA-CH), and the mechanical and degradation properties were analyzed. The BM-hMSCs were cultured in the scaffolds with the presence of growth medium (GM) or osteogenic medium (OM) with differentiation stimuli in combination with fetal bovine serum (FBS) or human platelet lysate (hPL). The primary objective was to determine the viability, proliferation, morphology, and spreading capacity of BM-hMSCs within the scaffolds, thereby confirming their biocompatibility. Secondly, the BM-hMSCs were shown to differentiate into osteoblasts and to facilitate scaffold mineralization. This was evinced by a positive Von Kossa result, the modulation of differentiation markers (osteocalcin and osteopontin), an expression of a marker of extracellular matrix remodeling (bone morphogenetic protein-2), and collagen I. The results of the energy-dispersive X-ray analysis (EDS) clearly demonstrate the presence of calcium and phosphorus in the samples that were incubated in OM, in the presence of FBS and hPL, but not in GM. The chemical distribution maps of calcium and phosphorus indicate that these elements are co-localized in the same areas of the sections, demonstrating the formation of hydroxyapatite. In conclusion, our findings show that the combination of BM-hMSCs and PLA-CH, regardless of the amount of hydrogel content, in the presence of differentiation stimuli, can provide a construct with enhanced osteogenicity for clinically relevant bone regeneration.

Optimizing Mesenchymal Stem Cells for Regenerative Medicine: Influence of Diabetes, Obesity, Autoimmune, and Inflammatory Conditions on Therapeutic Efficacy: A Review.

Mesenchymal stem cells (MSCs) are a promising tool that may be used in regenerative medicine. Thanks to their ability to differentiate and paracrine signaling, they can be used in the treatment of many diseases. Undifferentiated MSCs can support the regeneration of surrounding tissues through secreted substances and exosomes. This is possible thanks to the production of growth factors. These factors stimulate the growth of neighboring cells, have an anti-apoptotic effect, and support angiogenesis, and MSCs also have an immunomodulatory effect. The level of secreted factors may vary depending on many factors. Apart from the donor's health condition, it is also influenced by the source of MSCs, methods of harvesting, and even the banking of cells. This work is a review of research on how the patient's health condition affects the properties of obtained MSCs. The review discusses the impact of the patient's diabetes, obesity, autoimmune diseases, and inflammation, as well as the impact of the source of MSCs and methods of harvesting and banking cells on the phenotype, differentiation capacity, anti-inflammatory, angiogenic effects, and proliferation potential of MSCs. Knowledge about specific clinical factors allows for better use of the potential of stem cells and more appropriate targeting of procedures for collecting, multiplying, and banking these cells, as well as for their subsequent use. This article aims to review the characteristics, harvesting, banking, and paracrine signaling of MSCs and their role in diabetes, obesity, autoimmune and inflammatory diseases, and potential role in regenerative medicine.

Intracellular calcium dysregulation in heart and brain diseases: Insights from induced pluripotent stem cell studies.

The central nervous system (CNS) plays a role in regulating heart rate and myocardial contractility through sympathetic and parasympathetic nerves, and the heart can impact the functional equilibrium of the CNS through feedback signals. Although heart and brain diseases often coexist and mutually influence each other, the potential links between heart and brain diseases remain unclear due to a lack of reliable models of these relationships. Induced pluripotent stem cells (iPSCs), which can differentiate into multiple functional cell types, stem cell biology and regenerative medicine may offer tools to clarify the mechanisms of these relationships and facilitate screening of effective therapeutic agents. Because calcium ions play essential roles in regulating both the cardiovascular and nervous systems, this review addresses how recent iPSC disease models reveal how dysregulation of intracellular calcium might be a common pathological factor underlying the relationships between heart and brain diseases.

Evolving trends in stem cell therapy: an emerging and promising approach against various diseases

Stem cell therapy is growing in popularity as a form of regenerative medicine with the capacity to treat a wide range of ailments. Stem cells exhibit the ability to differentiate into a diverse array of cell types within the organism due to their undifferentiated state. These cell sources include bone marrow, induced pluripotent stem cells, and umbilical cord tissue 1. Significant advancements in clinical applications and fundamental research of stem cells in regenerative medicine and other domains have occurred in recent years, motivating individuals to delve deeper into the study of stem cells. Stem cells, owing to their virtually limitless capacity for self-renewal, offer vast potential for advancements in the treatment of various diseases and human organ damage. Stem cell-related technologies for induction and isolation are relatively developed in the field of stem cell research, and numerous stable stem cell lines have been constructed with outstanding results 2. This editorial will delve into the latest advancements in stem cell therapy, shedding light on key developments, their clinical applications, and the promising future prospects.

Hypoimmunogenic human iPSCs expressing HLA-G, PD-L1, and PD-L2 evade innate and adaptive immunity

BackgroundThe human induced pluripotent stem cells (hiPSCs) can generate all the cells composing the human body, theoretically. Therefore, hiPSCs are thought to be a candidate source of stem cells for regenerative medicine. The major challenge of allogeneic hiPSC-derived cell products is their immunogenicity. The hypoimmunogenic cell strategy is allogenic cell therapy without using immune suppressants. Advances in gene engineering technology now permit the generation of hypoimmunogenic cells to avoid allogeneic immune rejection. In this study, we generated a hypoimmunogenic hiPSC (HyPSC) clone that had diminished expression of human leukocyte antigen (HLA) class Ia and class II and expressed immune checkpoint molecules and a safety switch.MethodsFirst, we generated HLA class Ia and class II double knockout (HLA class Ia/II DKO) hiPSCs. Then, a HyPSC clone was generated by introducing exogenous β-2-microglobulin (B2M), HLA-G, PD-L1, and PD-L2 genes, and the Rapamycin-activated Caspase 9 (RapaCasp9)-based suicide gene as a safety switch into the HLA class Ia/II DKO hiPSCs. The characteristics and immunogenicity of the HyPSCs and their derivatives were analyzed.ResultsWe found that the expression of HLA-G on the cell surface can be enhanced by introducing the exogenous HLA-G gene along with B2M gene into HLA class Ia/II DKO hiPSCs. The HyPSCs retained a normal karyotype and had the characteristics of pluripotent stem cells. Moreover, the HyPSCs could differentiate into cells of all three germ layer lineages including CD45+ hematopoietic progenitor cells (HPCs), functional endothelial cells, and hepatocytes. The HyPSCs-derived HPCs exhibited the ability to evade innate and adaptive immunity. Further, we demonstrated that RapaCasp9 could be used as a safety switch in vitro and in vivo.ConclusionThe HLA class Ia/II DKO hiPSCs armed with HLA-G, PD-L1, PD-L2, and RapaCasp9 molecules are a potential source of stem cells for allogeneic transplantation.

A gene edited pig model for studying LGR5+ stem cells: implications for future applications in tissue regeneration and biomedical research.

Recent advancements in genome editing techniques, notably CRISPR-Cas9 and TALENs, have marked a transformative era in biomedical research, significantly enhancing our understanding of disease mechanisms and helping develop novel therapies. These technologies have been instrumental in creating precise animal models for use in stem cell research and regenerative medicine. For instance, we have developed a transgenic pig model to enable the investigation of LGR5-expressing cells. The model was designed to induce the expression of H2B-GFP under the regulatory control of the LGR5 promoter via CRISPR/Cas9-mediated gene knock-in. Notably, advancements in stem cell research have identified distinct subpopulations of LGR5-expressing cells within adult human, mouse, and pig tissues. LGR5, a leucine-rich repeat-containing G protein-coupled receptor, enhances WNT signaling and these LGR5+ subpopulations demonstrate varied roles and anatomical distributions, underscoring the necessity for suitable translational models. This transgenic pig model facilitates the tracking of LGR5-expressing cells and has provided valuable insights into the roles of these cells across different tissues and species. For instance, in pulmonary tissue, Lgr5+ cells in mice are predominantly located in alveolar compartments, driving alveolar differentiation of epithelial progenitors via Wnt pathway activation. In contrast, in pigs and humans, these cells are situated in a unique sub-basal position adjacent to the airway epithelium. In fetal stages a pattern of LGR5 expression during lung bud tip formation is evident in humans and pigs but is lacking in mice. Species differences with respect to LGR5 expression have also been observed in the skin, intestines, and cochlea further reinforcing the need for careful selection of appropriate translational animal models. This paper discusses the potential utility of the LGR5+ pig model in exploring the role of LGR5+ cells in tissue development and regeneration with the goal of translating these findings into human and animal clinical applications.

Conditioned Media Therapy in Alzheimer's Disease: Current Findings and Future Challenges.

Alzheimer's disease (AD) is a neurodegenerative disorder accompanied by a reduction in cognition and memory. Till now, there is no definite cure for AD, although, there are treatments available that may improve some symptoms. Currently, in regenerative medicine stem cells are widely used, mainly for treating neurodegenerative diseases. There are numerous forms of stem cells to treat AD aiming at the expansion of the treatment methods for this particular disease. Since 10 years ago, science has gained abundant knowledge to treat AD by understanding the sorts of stem cells, methods, and phasing of injection. Besides, due to the side effects of stem cell therapy like the potentiation for cancer, and as it is hard to follow the cells through the matrix of the brain, researchers have presented a new therapy for AD. They prefer to use conditioned media (CM) that are full of different growth factors, cytokines, chemokines, enzymes, etc. without tumorigenicity or immunogenicity such as stem cells. Another benefit of CM is that CM could be kept in the freezer, easily packaged, and transported, and doesn't need to fit with the donor. Due to the beneficial effects of CM, in this paper, we intend to evaluate the effects of various types of CM of stem cells on AD.

A global bibliometric and visual analysis of research on premature ovarian failure: Based on the perspective of stem cells.

Premature ovarian failure (POF), a condition influenced by genetic and immune factors, remains incurable despite years of intensive research and significant efforts. This persisting challenge underscores the urgency to address this escalating health concern. Fortunately, stem cell regenerative medicine has emerged as a promising avenue for developing therapeutic strategies and innovative treatments for POF. Bibliometric analysis, renowned for its objectivity, systematic approach, and comprehensive coverage of a given field, has yet to be applied to the study of stem cell research in POF. This study used CiteSpace software to assess contributions and co-occurrence relationships among various countries/regions, institutes, journals, and authors. This approach also allowed us to identify research hotspots and promising future trends within this field. Additionally, we generated visualizing maps utilizing the Web of Science Core Collection (WOSCC) and PubMed publications. By providing valuable information and references, we aim to enhance the understanding of the challenges involved in translating stem cell regeneration into clinical therapeutic potential for POF. Furthermore, our analysis and findings guide researchers and clinicians, facilitating future collaborative research and clinical intervention efforts.

Industry updates from the field of stem cell research and regenerative medicine in March 2024.

Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from non-academic institutions in March 2024.

Donor-Recipient Chimeric Cell Transplantation as the Bridging Therapy for Mitigating Total Body Irradiation-Induced Injury.

In recent years, cell-based therapies have emerged as a promising approach for mitigating radiation-induced injury. Acute radiation syndrome (ARS) results from exposure to high doses of radiation over a short time period. This study aimed to compare the efficacy of donor-recipient chimeric cell (DRCC) therapy in mitigating ARS induced by a total body irradiation (TBI) dose of 10 gray (Gy). Thirty irradiated Lewis rats were employed as ARS models to assess the efficacy of systemic-intraosseous transplantation of different cellular therapies in five experimental groups (n = 6/group): saline control, isogenic bone marrow transplantation (isoBMT), allogeneic BMT (alloBMT), DRCC, and alloBMT+DRCC. DRCC were created by polyethylene glycol-mediated fusion of bone marrow cells from 24 ACI (RT1a) and 24 Lewis (RT11) rat donors. The creation of DRCC and chimeric state was confirmed by flow cytometry (FC) and confocal microscopy (CM). Recovery of blood parameters was evaluated through complete blood count analysis. Graft-versus-host disease (GvHD) signs were assessed clinically and histopathologically using kidney, skin, and small intestine biopsies. FC and CM confirmed the fusion feasibility and the chimeric state of DRCC. A 100% mortality rate was observed in the saline control group, whereas a 100% survival was recorded following DRCC transplantation, correlating with significant recovery of peripheral blood parameters. In addition, no clinical or histopathological signs of GvHD were observed after DRCC and alloBMT+DRCC transplantation. These findings confirm efficacy of DRCC in mitigating GvHD, promoting hematopoietic recovery, and increasing animal survival following TBI-induced ARS. Moreover, tolerogenic and immunomodulatory properties of DRCC therapy support its feasibility for clinical applications. Therefore, this study introduces DRCC as an innovative bridging therapy for alleviating the acute effects of TBI, with broad implications for stem cell research and regenerative medicine.

Industry updates from the field of stem cell research and regenerative medicine in February 2024.

Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from non-academic institutions in February 2024.

Expansion of human umbilical cord derived mesenchymal stem cells in regenerative medicine.

Stem cells are undifferentiated cells that possess the potential for self-renewal with the capacity to differentiate into multiple lineages. In humans, their limited numbers pose a challenge in fulfilling the necessary demands for the regeneration and repair of damaged tissues or organs. Studies suggested that mesenchymal stem cells (MSCs), necessary for repair and regeneration via transplantation, require doses ranging from 10 to 400 million cells. Furthermore, the limited expansion of MSCs restricts their therapeutic application. To optimize a novel protocol to achieve qualitative and quantitative expansion of MSCs to reach the targeted number of cells for cellular transplantation and minimize the limitations in stem cell therapy protocols. Human umbilical cord (hUC) tissue derived MSCs were obtained and re-cultured. These cultured cells were subjected to the following evaluation procedures: Immunophenotyping, immunocytochemical staining, trilineage differentiation, population doubling time and number, gene expression markers for proliferation, cell cycle progression, senescence-associated β-galactosidase assay, human telomerase reverse transcriptase (hTERT) expression, mycoplasma, cytomegalovirus and endotoxin detection. Analysis of pluripotent gene markers Oct4, Sox2, and Nanog in recultured hUC-MSC revealed no significant differences. The immunophenotypic markers CD90, CD73, CD105, CD44, vimentin, CD29, Stro-1, and Lin28 were positively expressed by these recultured expanded MSCs, and were found negative for CD34, CD11b, CD19, CD45, and HLA-DR. The recultured hUC-MSC population continued to expand through passage 15. Proliferative gene expression of Pax6, BMP2, and TGFb1 showed no significant variation between recultured hUC-MSC groups. Nevertheless, a significant increase (P < 0.001) in the mitotic phase of the cell cycle was observed in recultured hUC-MSCs. Cellular senescence markers (hTERT expression and β-galactosidase activity) did not show any negative effect on recultured hUC-MSCs. Additionally, quality control assessments consistently confirmed the absence of mycoplasma, cytomegalovirus, and endotoxin contamination. This study proposes the development of a novel protocol for efficiently expanding stem cell population. This would address the growing demand for larger stem cell doses needed for cellular transplantation and will significantly improve the feasibility of stem cell based therapies.

Exploring stem cell frontiers: definitions, challenges, and perspectives for regenerative medicine.

Each year, the European Summer School on Stem Cell Biology and Regenerative Medicine (SCSS) attracts early-career researchers and actively practicing clinicians who specialise in stem cell and regenerative biology. The 16th edition of this influential course took place from 12th to 19th September 2023 on the charming Greek island of Spetses. Focusing on important concepts and recent advances in stem cells, the distinguished faculty included experts spanning the spectrum from fundamental research to clinical trials to market-approved therapies. Alongside an academically intensive programme that bridges the various contexts of stem cell research, delegates were encouraged to critically address relevant questions in stem cell biology and medicine, including broader societal implications. Here, we present a comprehensive overview and key highlights from the SCSS 2023.

Dynamic Roles of Signaling Pathways in Maintaining Pluripotency of Mouse and Human Embryonic Stem Cells.

Culturing of mouse and human embryonic stem cells (ESCs) in vitro was a major breakthrough in the field of stem cell biology. These models gained popularity very soon mainly due to their pluripotency. Evidently, the ESCs of mouse and human origin share typical phenotypic responses due to their pluripotent nature, such as self-renewal capacity and potency. The conserved network of core transcription factors regulates these responses. However, significantly different signaling pathways and upstream transcriptional networks regulate expression and activity of these core pluripotency factors in ESCs of both the species. In fact, ample evidence shows that a pathway, which maintains pluripotency in mouse ESCs, promotes differentiation in human ESCs. In this review, we discuss the role of canonical signaling pathways implicated in regulation of pluripotency and differentiation particularly in mouse and human ESCs. We believe that understanding these distinct and at times-opposite mechanisms-is critical for the progress in the field of stem cell biology and regenerative medicine.

The biological characteristics of chicken embryo mesenchymal stem cells isolated from chorioallantoic membrane.

Mesenchymal stem cells (MSCs) derived from fetal membranes (FMs) have the potential to exhibit immunosuppression, improve blood flow, and increase capillary density during transplantation. In the field of medicine, opening up new avenues for disease treatment. Chicken embryo chorioallantoic membrane (CAM), as an important component of avian species FM structure, has become a stable tissue engineering material in vivo angiogenesis, drug delivery, and toxicology studies. Although it has been confirmed that chorionic mesenchymal stem cells (Ch-MSCs) can be isolated from the outer chorionic layer of FM, little is known about the biological characteristics of MSCs derived from chorionic mesodermal matrix of chicken embryos. Therefore, we evaluated the characteristics of MSCs isolated from chorionic tissues of chicken embryos, including cell proliferation ability, stem cell surface antigen, genetic stability, and in vitro differentiation potential. Ch-MSCs exhibited a broad spindle shaped appearance and could stably maintain diploid karyotype proliferation to passage 15 in vitro. Spindle cells were positive for multifunctional markers of MSCs (CD29, CD44, CD73, CD90, CD105, CD166, OCT4, and NANOG), while hematopoietic cell surface marker CD34, panleukocyte marker CD45, and epithelial cell marker CK19 were negative. In addition, chicken Ch-MSC was induced to differentiate into four types of mesodermal cells in vitro, including osteoblasts, chondrocytes, adipocytes, and myoblasts. Therefore, the differentiation potential of chicken Ch-MSC in vitro may have great potential in tissue engineering. In conclusion, chicken Ch-MSCs may be an excellent model cell for stem cell regenerative medicine and chorionic tissue engineering.