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Signal Transduction and Targeted Therapy Jan 2024Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes... (Review)
Review
Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.
Topics: Exosomes; Mesenchymal Stem Cells; Induced Pluripotent Stem Cells; Embryonic Stem Cells
PubMed: 38212307
DOI: 10.1038/s41392-023-01704-0 -
Cell Communication and Signaling : CCS Aug 2023Chimeric antigen receptors (CARs) are widely used by T cells (CAR-T cells), natural killer cells dendritic cells and macrophages, and they are of great importance in... (Review)
Review
Chimeric antigen receptors (CARs) are widely used by T cells (CAR-T cells), natural killer cells dendritic cells and macrophages, and they are of great importance in cellular immunotherapy. However, the use of CAR-related products faces several challenges, including the poor persistence of cells carrying CARs, cell dysfunction or exhaustion, relapse of disease, immune effector cell-associated neurotoxicity syndrome, cytokine release syndrome, low efficacy against solid tumors and immunosuppression by the tumor microenvironment. Another important cell therapy regimen involves mesenchymal stem cells (MSCs). Recent studies have shown that MSCs can improve the anticancer functions of CAR-related products. CAR-MSCs can overcome the flaws of cellular immunotherapy. Thus, MSCs can be used as a biological vehicle for CARs. In this review, we first discuss the characteristics and immunomodulatory functions of MSCs. Then, the role of MSCs as a source of exosomes, including the characteristics of MSC-derived exosomes and their immunomodulatory functions, is discussed. The role of MSCs in CAR-related products, CAR-related product-derived exosomes and the effect of MSCs on CAR-related products are reviewed. Finally, the use of MSCs as CAR vehicles is discussed. Video Abstract.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Immunotherapy; Neoplasms; Mesenchymal Stem Cells; Tumor Microenvironment
PubMed: 37528472
DOI: 10.1186/s12964-023-01191-4 -
Advanced Science (Weinheim,... Nov 2023Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that...
Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism in these processes remains unclear. The present study finds that ovariectomized mice exhibit reduced blood vessel density in the bone and reduced expression of the endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Endothelial cell (EC)-specific deletion of Pkm2 impairs osteogenesis and worsens osteoporosis in mice. This is attributed to the impaired ability of bone mesenchymal stem cells (BMSCs) to differentiate into osteoblasts. Mechanistically, EC-specific deletion of Pkm2 reduces serum lactate levels secreted by ECs, which affect histone lactylation in BMSCs. Using joint CUT&Tag and RNA sequencing analyses, collagen type I alpha 2 chain (COL1A2), cartilage oligomeric matrix protein (COMP), ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7 like 2 (TCF7L2) as osteogenic genes regulated by histone H3K18la lactylation are identified. PKM2 overexpression in ECs, lactate addition, and exercise restore the phenotype of endothelial PKM2-deficient mice. Furthermore, serum metabolomics indicate that patients with osteoporosis have relatively low lactate levels. Additionally, histone lactylation and related osteogenic genes of BMSCs are downregulated in patients with osteoporosis. In conclusion, glycolysis in ECs fuels BMSC differentiation into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis by increasing serum lactate levels.
Topics: Humans; Animals; Mice; Histones; Lactic Acid; Osteoporosis; Mesenchymal Stem Cells; Endothelial Cells
PubMed: 37752768
DOI: 10.1002/advs.202301300 -
Science Advances Jul 2023Pulmonary fibrosis (PF) is an age-related interstitial lung disease that results in notable morbidity and mortality. The Food and Drug Administration-approved drugs can...
Pulmonary fibrosis (PF) is an age-related interstitial lung disease that results in notable morbidity and mortality. The Food and Drug Administration-approved drugs can decelerate the progression of PF; however, curing aged patients with severe fibrosis is ineffective because of insufficient accumulation of these drugs and wide necrocytosis of type II alveolar epithelial cells (AEC IIs). Here, we constructed a mesenchymal stem cell (MSC)-based nanoengineered platform via the bioconjugation of MSCs and type I collagenase-modified liposomes loaded with nintedanib (MSCs-Lip@NCAF) for treating severe fibrosis. Specifically, MSCs-Lip@NCAF migrated to fibrotic lungs because of the homing characteristic of MSCs and then Lip@NCAF was sensitively released. Subsequently, Lip@NCAF ablated collagen fibers, delivered nintedanib into fibroblasts, and inhibited fibroblast overactivation. MSCs differentiated into AEC IIs to repair alveolar structure and ultimately promote the regeneration of damaged lungs in aged mice. Our findings indicated that MSCs-Lip@NCAF could be used as a promising therapeutic candidate for PF therapy, especially in aged patients.
Topics: United States; Animals; Mice; Pulmonary Fibrosis; Mesenchymal Stem Cell Transplantation; Lung; Alveolar Epithelial Cells; Mesenchymal Stem Cells
PubMed: 37467328
DOI: 10.1126/sciadv.adg5358 -
Advanced Science (Weinheim,... Oct 2023Wound healing is an urgent clinical challenge, particularly in the case of chronic wounds. Traditional approaches to wound healing have limited therapeutic efficacy due...
Wound healing is an urgent clinical challenge, particularly in the case of chronic wounds. Traditional approaches to wound healing have limited therapeutic efficacy due to lengthy healing times, risk of immune rejection, and susceptibility to infection. Recently, adipose-derived mesenchymal stem cell-derived exosomes (ADSC-exos) have emerged as a promising modality for tissue regeneration and wound repair. In this study, the development of a novel extracellular matrix hydrogel@exosomes (ECM@exo) is reported, which entails incorporation of ADSC-exos into an extracellular matrix hydrogel (ECM hydrogel). This solution forms a hydrogel at physiological temperature (≈37 °C) upon local injection into the wound site. ECM@exo enables sustained release of ADSC-exos from the ECM hydrogel, which maintains high local concentrations at the wound site. The ECM hydrogel displays good biocompatibility and biodegradability. The in vivo and in vitro results demonstrate that ECM@exo treatment effectively reduces inflammation and promotes angiogenesis, collagen deposition, cell proliferation, and migration, thereby accelerating the wound healing process. Overall, this innovative therapeutic approach offers a new avenue for wound healing via a biological hydrogel with controlled exosome release.
Topics: Humans; Hydrogels; Exosomes; Wound Healing; Mesenchymal Stem Cells; Diabetes Mellitus; Extracellular Matrix
PubMed: 37712174
DOI: 10.1002/advs.202304023 -
Cells Apr 2024Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently... (Review)
Review
Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they come. In this work, the possibility of using MSCs to deliver therapeutic genes, oncolytic viruses, and miRNA is presented, as well as strategies that can improve their therapeutic efficacy against glioblastoma, such as CAR-T cells, nanoparticles, and exosomes.
Topics: Humans; Glioblastoma; Mesenchymal Stem Cell Transplantation; Glioma; Brain Neoplasms; Mesenchymal Stem Cells
PubMed: 38607056
DOI: 10.3390/cells13070617 -
The Journal of Clinical Investigation Aug 2023Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe...
Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. Hematopoietic dysfunction accompanied by severe aGVHD, which may be caused by niche impairment, is a long-standing clinical problem. However, how the bone marrow (BM) niche is damaged in aGVHD hosts is poorly defined. To comprehensively address this question, we used a haplo-MHC-matched transplantation aGVHD murine model and performed single-cell RNA-Seq of nonhematopoietic BM cells. Transcriptional analysis showed that BM mesenchymal stromal cells (BMSCs) were severely affected, with a reduction in cell ratio, abnormal metabolism, compromised differentiation potential, and defective hematopoiesis-supportive function, all of which were validated by functional assays. We found that ruxolitinib, a selective JAK1/2 inhibitor, ameliorated aGVHD-related hematopoietic dysfunction through a direct effect on recipient BMSCs, resulting in improved proliferation ability, adipogenesis/osteogenesis potential, mitochondria metabolism capacity, and crosstalk with donor-derived hematopoietic stem/progenitor cells. By inhibiting the JAK2/STAT1 pathway, ruxolitinib maintained long-term improvement of aGVHD BMSC function. Additionally, ruxolitinib pretreatment in vitro primed BMSCs to better support donor-derived hematopoiesis in vivo. These observations in the murine model were validated in patient samples. Overall, our findings suggest that ruxolitinib can directly restore BMSC function via the JAK2/STAT1 pathway and, in turn, improve the hematopoietic dysfunction caused by aGVHD.
Topics: Humans; Animals; Mice; Disease Models, Animal; Hematopoietic Stem Cell Transplantation; Graft vs Host Disease; Mesenchymal Stem Cells; Acute Disease
PubMed: 37338986
DOI: 10.1172/JCI162201 -
Physiological Reviews Apr 2024Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery,... (Review)
Review
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
Topics: Humans; Myocardial Infarction; Myocardium; Cardiovascular Physiological Phenomena; Heart Failure; Mesenchymal Stem Cells
PubMed: 37589393
DOI: 10.1152/physrev.00009.2023 -
Advanced Science (Weinheim,... Sep 2023Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis;...
Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis; however, therapeutic choices for this condition remain controversial. Mesenchymal stem cells (MSCs) are a family member of stem cells with immunomodulatory and anti-inflammatory capabilities that can mitigate damage in experimental pancreatitis. Here, it is shown that MSCs deliver hypoxia-treated functional mitochondria to damaged pancreatic acinar cells (PACs) via extracellular vesicles (EVs), which reverse the metabolic function of PACs, maintain ATP supply, and exhibit an excellent injury-inhibiting effect. Mechanistically, hypoxia inhibits superoxide accumulation in the mitochondria of MSCs and upregulates the membrane potential, which is internalized into PACs via EVs, thus, remodeling the metabolic state. In addition, cargocytes constructed via stem cell denucleation as mitochondrial vectors are shown to exert similar therapeutic effects to MSCs. These findings reveal an important mechanism underlying the role of mitochondria in MSC therapy and offer the possibility of applying mitochondrial therapy to patients with severe acute pancreatitis.
Topics: Acinar Cells; Acute Disease; Adenosine Triphosphate; Bile Acids and Salts; Cell Hypoxia; Cellular Reprogramming; Extracellular Vesicles; Membrane Potential, Mitochondrial; Mesenchymal Stem Cells; Mitochondria; Mitochondrial Permeability Transition Pore; Pancreas; Pancreatitis; Paracrine Communication; Superoxides; Umbilical Cord; Humans
PubMed: 37409821
DOI: 10.1002/advs.202207691 -
Cells May 2024Mesenchymal stem cells (MSCs) have garnered significant interest in the field of regenerative medicine for their ability to potentially treat various diseases,...
Mesenchymal stem cells (MSCs) have garnered significant interest in the field of regenerative medicine for their ability to potentially treat various diseases, especially neurodegenerative disorders [...].
Topics: Neurodegenerative Diseases; Humans; Mesenchymal Stem Cells; Mesenchymal Stem Cell Transplantation; Animals; Regenerative Medicine
PubMed: 38727315
DOI: 10.3390/cells13090779