Ischemic stroke results in significant long-term disability and mortality worldwide. Although existing therapies, such as recombinant tissue plasminogen activator and mechanical thrombectomy, have shown promise, their application is limited by stringent conditions. Mesenchymal stem cell (MSC) transplantation, especially using SB623 cells (modified human bone marrow-derived MSCs), has emerged as a promising alternative, promoting neurogenesis and recovery. This study evaluated the effects of voluntary and forced exercise, alone and in combination with SB623 cell transplantation, on neurological and psychological outcomes in a rat model of ischemic stroke. Male Wistar rats that had undergone middle cerebral artery occlusion (MCAO) were divided into six groups: control, voluntary exercise (V-Ex), forced exercise (F-Ex), SB623 transplantation, SB623 + V-Ex, and SB623 + F-Ex. Voluntary exercise was facilitated using running wheels, while forced exercise was conducted on treadmills. Neurological recovery was assessed using the modified neurological severity score (mNSS). Psychological symptoms were evaluated through the open field test (OFT) and forced swim test (FST), and neurogenesis was assessed via BrdU labeling. Both exercise groups exhibited significant changes in body weight post-MCAO. Both exercises enhanced the treatment effect of SB623 transplantation. The forced exercise showed a stronger treatment effect on ischemic stroke than voluntary exercise alone, and the sole voluntary exercise improved depression-like behavior. The SB623 + F-Ex group demonstrated the greatest improvements in motor function, infarct area reduction, and neurogenesis. The SB623 + V-Ex group was most effective in alleviating depression-like behavior. Future research should optimize these exercise protocols and elucidate the underlying mechanisms to develop tailored rehabilitation strategies for stroke patients.

Diabetic nephropathy (DN) is one of the most common microvascular complications of diabetes mellitus. Traditional treatment methods have certain limitations and it is difficult to effectively delay the disease progression. Mesenchymal stem cells (MSCs), owing to their potential for self-renewal, multidirectional differentiation, and immunomodulatory abilities, can regulate the renal immune microenvironment and repair damaged tissues, providing a new strategy for the treatment of DN. However, MSCs face problems such as immune rejection, cell inactivation, challenges in directed differentiation, insufficient homing ability, and low cell retention rate after delivery. These issues limit their clinical application in patients with DN. This review aims to propose optimization strategies targeting DN pathological features to improve MSC effectiveness and reduce their side effects. Specifically, it involves optimizing cell culture systems and cryopreservation protocols, along with pre-transplantation pharmacological conditioning to boost the functionality and viability of MSCs. Additionally, the exploration of synergistic drug-MSC combination therapies was carried out, taking advantage of diverse mechanisms of action to improve therapeutic outcomes. The integration of biomaterials and gene editing technologies to significantly enhance cell survival, target specificity, and tissue engraftment was also pursued. Concurrently, the determination of optimal therapeutic dosages and administration routes remained crucial. These multifaceted strategies not only provide a theoretical framework for overcoming existing technical limitations but also lay a robust foundation for accelerating the clinical translation of MSC-based therapies.

Cell therapy utilizing mesenchymal stromal cells (MSCs) through paracrine mechanisms holds promise for regenerative purposes. Peritoneal fibrosis (PF) is a significant complication of peritoneal dialysis. Various strategies have been proposed to protect the peritoneal membrane (PM). This study explores the effectiveness of adipose-tissue-derived stem cells (ASCs) and extracellular vesicles (EVs) at mitigating PF using a rat model of PF induced by chlorhexidine gluconate. ASC and EV treatments effectively prevented an increase in the thickness of the PM and diminished the number of myofibroblasts, fibronectin expression, collagen III expression, and PF-related factors such as TGF-β and FSP-1. Smad3 gene expression decreased in the treatment groups, whereas Smad7 gene expression increased in treated animals. In addition, ASC and EV injections showed potent anti-inflammatory effects. Glucose transport through the PM remained unaffected in relation to the PF group; both treatments promoted an increase in ultrafiltration (UF) capacity. The PF+EVs treated group showed the highest increase in UF capacity. Another critical aspect of ASC and EV treatments was their impact on neoangiogenesis in the PM which is vital for UF capacity. Although the treated groups displayed a significant decrease in VEGF expression in the PM, peritoneal function remained effective. In conclusion, within the experimental PF model, both ASC and EV treatments demonstrated anti-inflammatory effects and comparably hindered the progression of PF. The EV treatment exhibited superior preservation of peritoneal function, along with enhanced UF capacity. These findings suggest the potential of ASCs and EVs as novel therapeutic approaches to prevent the development of PF associated with peritoneal dialysis.

Cells cross the placenta during pregnancy, resulting in proliferation of semiallogeneic cells in the mother and fetus decades later. This phenomenon, termed microchimerism, is documented across mammalian species, implying an evolutionary benefit. Still, short- and long-term effects remain uncertain. Here, we review the dynamics of microchimerism of fetal, maternal, and mother of the proband origin in relation to increasing gestational age and pregnancy complications associated with placental dysfunction including preeclampsia, fetal growth restriction, preterm labor, recurrent miscarriage, and diabetes. We use the two-stage model of preeclampsia as a framework. We recently published a series of papers independently linking increased fetal microchimerism to markers of placental dysfunction (stage 1), severe maternal hypertension (stage 2) and poor glucose control. Placental dysfunction may influence the intrinsic properties of fetal stem cells. Mesenchymal and hematopoietic stem cells isolated from cord blood during preeclampsia display reduced proliferative potential in vitro. Moreover, preeclampsia is shown to disrupt paracrine signaling in mesenchymal stem cells of the umbilical cord. Undesired properties in cells transferred to the mother could have profound negative effects on maternal health. Finally, recent studies indicate that microchimerism is involved in inducing maternal-fetal tolerance. Disruption of this process is associated with pregnancy complications. Long term, the persistence of microchimerism is necessary to sustain specific regulatory T cell populations in mice. This likely plays a role in the proband's future pregnancies and long-term maternal and offspring health. Current evidence indicates that advancements in our understanding of microchimerism could be instrumental in promoting reproductive and long-term health.

Human mesenchymal stem cells (MSCs) have been widely studied and applied for the treatment of various diseases due to their crucial role in tissue repair and regeneration. Compared to MSCs isolated from somatic tissues, MSCs differentiated from human pluripotent stem cells (ps-MSCs) have demonstrated similar therapeutic effects while possessing some advantages in quality control and assurance, given their unlimited and consistent supply of source cells. This makes ps-MSCs highly druggable and promising for therapeutic applications. In this minireview, we introduce the latest progress in ps-MSC research, focusing on the therapeutic properties, origin, in vivo development, and application of ps-MSCs in cancer research. We will also discuss the perspectives and challenges of this relatively new source of MSCs.

Several cartilage and bone organoids have been developed in vitro and in vivo using adult mesenchymal stromal/stem cells (MSCs) or pluripotent stem cells (PSCs) to mimic different phases of endochondral ossification (ECO), as one of the main processes driving skeletal development and growth. While cellular and molecular features of growth plate-like structures have been observed through the generation and in vivo implantation of hypertrophic cartilage tissues, no functional analogue or model of the growth plate has yet been engineered. Herein, after a brief introduction about the growth plate architecture and function, we summarize the recent progress in dissecting the biology of the growth plate and indicate the knowledge gaps to better understand the mechanisms of its development and maintenance. We then discuss how this knowledge could be integrated with state-of-art bioengineering approaches to generate a functional in vitro growth plate model.

The skin is a complex organ that includes various stem cell populations. Current approaches for non-healing skin defects are sometimes inadequate and many attempts have been made to regenerate skin integrity. The aim of this review is to bridge the gap between basic research and clinical application of skin integrity regeneration.

A literature search was carried out in PubMed using combinations of the keywords "skin integrity", "tissue-engineered skin", "bioengineered skin", and "skin regeneration". Articles published from 1968 to 2023 reporting evidence from in vivo and in vitro skin regeneration experiments were included.

These articles showed that stem cells can be differentiated into normal skin cells, including keratinocytes, and are a significant source of skin organoids, which are useful for investigating skin biology; and that emerging direct reprogramming methods have great potential to regenerate skin from the wounded skin surface.

Recent advances in skin regeneration will facilitate further advancement of both basic and clinical research in skin biology.

The need for large-scale production of mesenchymal stromal cell (MSC)-based cellular therapeutics continues to grow around the globe. Manual cell expansion processes can be highly variable between operators, require significant hands-on time from skilled staff and, because of the large number of open manipulation steps required to produce cells in dose-relevant quantities, be prone to greater risk of contamination relative to automated processes. All of these can increase overall production costs and risks to the patient. In order to meet the needs of this growing industry, viable options for large-scale automation coupled with consistent and compliant ancillary materials needed to drive cell expansion are needed.

In the work described herein, the automated and functionally closed hollow-fiber bioreactor system Quantum Flex (Terumo Blood and Cell Technologies, Inc., Lakewood, CO, USA) was used in conjunction with Good Manufacturing Practice (GMP)-compliant, virus-inactivated human fibronectin (FN) from Akron Bio (Boca Raton, FL, USA) to expand MSCs to clinically relevant numbers. In order to assess the performance of Akron Bio's GMP-grade FN, use of this product in the production of MSCs was referenced against use of a research-use-only (RUO)-grade FN product used extensively for MSC expansion in Quantum. Because many MSC-based processes require passaging of cells to attain the appropriate number of cells needed, a two-passage process was employed comparing the transfer of MSCs expanded on RUO FN to RUO FN, GMP FN to GMP FN and RUO FN to GMP FN to assess the impacts of transitioning from one grade of FN to another, as a product might be required to do as it moves from pre-clinical to clinical stages and beyond.

No statistically significant differences were noted when MSCs were transferred from RUO FN to RUO FN, GMP FN to GMP FN or RUO FN to GMP FN in terms of harvest yield, population doubling time, seeding efficiency estimates or fold expansion. All MSCs harvested from all groups met International Society for Cell & Gene Therapy standards for MSCs in terms of protein marker expression measured by flow cytometry, adherence to plastic, downstream cell morphology and trilineage differentiation.

The combination of Quantum Flex as an expansion platform and Akron Bio's GMP FN is seen as an attractive option for larger-scale manufacture of GMP-grade MSC products.

Mesenchymal stromal cells (MSCs) and stem cells are distinct types of cells, but they are practically undistinguishable by currently commonly-used identification markers. A single-cell transcriptomic analysis was used to solve this problem. There are eight critical genes involved in self-renewal and differentiation, SOX2, NANOG, POU5F1, SFRP2, DPPA4, SALL4, ZFP42 and MYCN expressed in ESCs, iPSCs and adult stem cells (ASCs), but not in MSCs. There are five functional genes of MSCs, TMEM119, FBLN5, KCNK2, CLDN11 and DKK1, which are not expressed in stem cells. Trajectory analysis displayed clear developmental cliffs from ESCs/iPSCs to ASCs and to MSCs. Adipose-derived MSCs, relative to other types of MSCs, exhibit a more consistent and broader spectrum of gene expression for regulatory and excrete function. This study identifies distinction markers between MSCs and stem cells, providing an alternative approach for quality control of MSCs in their propagation and further mechanistic insights into their action.

Erectile dysfunction is a common and multifactorial condition that significantly impacts men's quality of life. Traditional treatments, such as phosphodiesterase type 5 inhibitors (PDE5i), often fail to provide lasting benefits, particularly in patients with underlying health conditions. In recent years, regenerative medicine, particularly stem cell therapies, has emerged as a promising alternative for managing erectile dysfunction. This review explores the potential of mesenchymal stromal/stem cells (MSCs) and their paracrine effects, including extracellular vesicles (EVs), in the treatment of erectile dysfunction. MSCs have shown remarkable potential in promoting tissue repair, reducing inflammation, and regenerating smooth muscle cells, offering therapeutic benefits in models of erectile dysfunction. Clinical trials have demonstrated positive outcomes in improving erectile function and other clinical parameters. This review highlights the promise of MSC therapy for erectile dysfunction, discusses existing challenges, and emphasizes the need for continued research to refine these therapies and improve long-term patient outcomes.

Lymphoid leukemias represent a significant global health burden, leading to substantial morbidity and mortality. The intricate interplay between leukemic cells and their surrounding tumor microenvironment (TME) is pivotal in disease initiation, progression, and therapeutic resistance. Comprising a dynamic milieu of stromal, immune, and leukemic cell populations, the TME orchestrates a complex network of signaling pathways and molecular interactions that foster leukemic cell survival and proliferation while evading immune surveillance. The crosstalk between these diverse cellular components within the TME not only fuels tumor progression but also confers resistance to conventional therapies, including the development of multi-drug resistance (MDR). Recognizing the pivotal role of the TME in shaping disease outcomes, novel therapeutic approaches targeting this dynamic ecosystem have emerged as promising strategies to complement existing anti-leukemic treatments. As a result, drugs that target the TME have been developed as complementary strategies to those that directly attack tumor cells. Thus, a detailed understanding of the TME components and their interactions with tumor cells is critical. Such knowledge can guide the design and implementation of novel targeted therapies for lymphoid leukemias.

In recent years, the therapeutic utility of mesenchymal stem cells (MSCs) has received substantial attention from investigators, owing to their pleiotropic properties. The emerging insights from the developments in tissue engineering provide perspectives for the repair of damaged tissue and the replacement of failing organs. Perivascular cells including MSC-like pericytes, vascular smooth muscles, and other cells located around blood vessels, have been acknowledged to contribute to in situ angiogenesis and repair process. MSCs offer a wide array of therapeutic applications in different pathological states. However, in the current article, we have highlighted the recent updates on MSCs and their key applications in cardiac and cerebrovascular diseases, evident in different preclinical and clinical studies. We believe the present article would assist the investigators in understanding the recent advances of MSCs and exploring their therapeutic potential in varied ailments, especially cardiac and cerebrovascular diseases.

Autoimmune diseases are characterized by immune dysregulation, resulting in aberrant reactivity of T cells and antibodies to self-antigens, leading to various patterns of inflammation and organ dysfunction. However, current therapeutic agents exhibit broad-spectrum activity and lack disease-specific selectivity, leading to enduring adverse effects, notably severe infections, and malignancies, and patients often fail to achieve the intended clinical goals. Mesenchymal stromal cells (MSCs) are multipotent stromal cells that can be easily derived from various tissues, such as adipose tissue, umbilical cords, Wharton's jelly, placenta, and dental tissues. MSCs offer advantages due to their immunomodulatory and anti-inflammatory abilities, low immunogenicity, and a high capacity for proliferation and multipotent differentiation, making them excellent candidates for cell-based treatment in autoimmune disorders. This review will cover preclinical studies and clinical trials involving MSCs in autoimmune diseases, as well as the primary challenges associated with the clinical application of MSC therapies and strategies for maximizing their therapeutic potential.

Major depressive disorder (MDD) is considered a psychiatric disorder and have a relationship with stressful events. Although the common therapeutic approaches against MDD are diverse, a large number of patients do not present an adequate response to antidepressant treatments. On the other hand, effective non-pharmacological treatments for MDD and their tolerability are addressed. Several affective treatments for MDD are used but non-pharmacological strategies for decreasing the common depression-related drugs side effects have been focused recently. However, the potential of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs), microRNAs (miRNAs) as cell-based therapeutic paradigms, besides other non-pharmacological strategies including mitochondrial transfer, plasma, transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), and exercise therapy needs to further study. This review explores the therapeutic potential of cell-based therapeutic non-pharmacological paradigms for MDD treatment. In addition, plasma therapy, mitotherapy, and exercise therapy in several in vitro and in vivo conditions in experimental disease models along with tDCS and TMS will be discussed as novel non-pharmacological promising therapeutic approaches.

➢ Skeletal stem cells (SSCs) continually replenish mature cell populations to support skeletal homeostasis.➢ SSCs repopulate by self-renewal, have multilineage potential, and are long-lived in vivo.➢ SSCs express specific combinations of cell surface markers that reflect their lineage identity.➢ SSCs adapt to their anatomic environment to support regional differences in skeletal behavior and pathology.

Mesenchymal stem/stromal cells (MSCs) have garnered attention for their potential in cancer therapy due to their ability to home to tumor sites. Engineered MSCs have been developed to deliver therapeutic proteins, microRNAs, prodrugs, chemotherapy drugs, and oncolytic viruses directly to the tumor microenvironment, with the goal of enhancing therapeutic efficacy while minimizing off-target effects. Despite promising results in preclinical studies and clinical trials, challenges such as variability in delivery efficiency and safety concerns persist. Ongoing research aims to optimize MSC-based cancer eradication and immunotherapy, enhancing their specificity and efficacy in cancer treatment. This review focuses on advancements in engineering MSCs for tumor-targeted therapy.

Tuberous sclerosis complex is a genetic disorder caused by mutations in the TSC1 or TSC2 genes, affecting multiple systems. These genes produce proteins that regulate mTORC1 activity, essential for cell function and metabolism. While mTOR inhibitors have advanced treatment, maintaining long-term therapeutic success is still challenging. For over 20 years, significant progress has linked TSC1 or TSC2 gene mutations in stem cells to tuberous sclerosis complex symptoms.

A comprehensive review was conducted using databases like Web of Science, Google Scholar, PubMed, and Science Direct, with search terms such as "tuberous sclerosis complex," "TSC1," "TSC2," "stem cell," "proliferation," and "differentiation." Relevant literature was thoroughly analyzed and summarized to present an updated analysis of the TSC1-TSC2 complex's role in stem cell fate determination and its implications for tuberous sclerosis complex.

The TSC1-TSC2 complex plays a crucial role in various stem cells, such as neural, germline, nephron progenitor, intestinal, hematopoietic, and mesenchymal stem/stromal cells, primarily through the mTOR signaling pathway.

This review aims shed light on the role of the TSC1-TSC2 complex in stem cell fate, its impact on health and disease, and potential new treatments for tuberous sclerosis complex.

Multiple sclerosis (MS), a chronic autoimmune disorder of the central nervous system (CNS), is characterized by inflammation, demyelination, and neurodegeneration, leading to diverse clinical manifestations such as fatigue, sensory impairment, and cognitive dysfunction. Current pharmacological treatments primarily target immune modulation but fail to arrest disease progression or entirely reverse CNS damage. Mesenchymal stem cell (MSC) therapy offers a promising alternative, leveraging its immunomodulatory, neuroprotective, and regenerative capabilities. This review provides an in-depth analysis of MSC mechanisms of action, including immune system regulation, promotion of remyelination, and neuroregeneration. It examines preclinical studies and clinical trials evaluating the efficacy, safety, and limitations of MSC therapy in various MS phenotypes. Special attention is given to challenges such as delivery routes, dosing regimens, and integrating MSCs with conventional therapies. By highlighting advancements and ongoing challenges, this review underscores the potential of MSCs to revolutionize MS treatment, paving the way for personalized and combinatory therapeutic approaches.

Bone tissue engineering is a promising field that aims to rebuild the bone tissue using biomaterials, cells, and signaling molecules. Materials like natural and synthetic polymers, inorganic materials, and composite materials are used to create scaffolds that mimic the hierarchical microstructure of bone. Stem cells, particularly mesenchymal stem cells (MSCs), play a crucial role in bone tissue engineering by promoting tissue regeneration and modulating the immune response. Growth factors like bone morphogenetic proteins (BMPs), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF) are utilized to accelerate bone regeneration. Clinical applications include treating nonunion and mal-union fractures, osteonecrosis, orthopedic surgery, dental applications, and spinal cord injuries. Recent advances in the field include nanotechnology, 3D printing, bioprinting techniques, gene editing technologies, and microfluidic devices for drug testing. However, challenges remain, such as standardization of protocols, large-scale biomaterial production, personalized medicine approaches, cost-effectiveness, and regulatory issues. Current clinical trials are investigating the safety and efficacy of various bone tissue engineering approaches, with the potential to modernize patient care by providing more adequate treatments for bone defects and injuries.

The management of segmental bone defects presents a complex reconstruction challenge for orthopedic surgeons. Current treatment options are limited by efficacy across the spectrum of injury, morbidity, and cost. Regional gene therapy is a promising tissue engineering strategy for bone repair, as it allows for local implantation of nucleic acids or genetically modified cells to direct specific protein expression. In cell-based gene therapy approaches, a variety of different cell types have been described including mesenchymal stem cells (MSCs) derived from multiple sources-bone marrow, adipose, skeletal muscle, and umbilical cord tissue, among others. MSCs, in particular, have been well studied, as they serve as a source of osteoprogenitor cells in addition to providing a vehicle for transgene delivery. Furthermore, MSCs possess immunomodulatory properties, which may support the development of an allogeneic "off-the-shelf" gene therapy product. Identifying an optimal cell type is paramount to the successful clinical translation of cell-based gene therapy approaches. Here, we review current strategies for the management of segmental bone loss in orthopedic surgery, including bone grafting, bone graft substitutes, and operative techniques. We also highlight regional gene therapy as a tissue engineering strategy for bone repair, with a focus on cell types and cell sources suitable for this application.

Interaction between mesenchymal stem cells (MSCs) and oral squamous cell carcinoma (OSCC) cells plays a major role in OSCC progression. However, little is known about adipogenic differentiation alteration in OSCC-derived MSCs (OSCC-MSCs) and how these alterations affect OSCC growth.

MSCs were successfully isolated and cultured from normal gingival tissue, OSCC peritumoral tissue, and OSCC tissue. This included gingiva-derived MSCs (GMSCs), OSCC adjacent noncancerous tissues-derived MSCs (OSCCN-MSCs), and OSCC-MSCs. The adipogenic and osteogenic differentiation capabilities of these cells were evaluated using Oil Red O and Alizarin Red S staining, respectively. OSCC cells were then co-cultured with either OSCC-MSCs or GMSCs to assess the impact on OSCC cell proliferation and migration. Subcutaneous xenograft experiments were conducted in BALB/c-nu mice to further investigate the effects in vivo. Additionally, immunohistochemical staining was performed on clinical samples to determine the expression levels of fatty acid synthase (FASN) and the proliferation marker Ki67.

OSCC-MSCs exhibited enhanced adipogenic differentiation and reduced osteogenic differentiation compared to GMSCs. OSCC-MSCs significantly increased the proliferation and migration of OSCC cells relative to GMSCs and promoted tumor growth in mouse xenografts. Lipid droplet accumulation in the stroma was significantly more pronounced in OSCC + OSCC-MSCs xenografts compared to OSCC + GMSCs xenografts. Free fatty acids (FFAs) levels were elevated in OSCC tissues compared to normal gingival tissues. Moreover, OSCC-MSCs consistently secreted higher levels of FFAs in condition medium than GMSCs. Knockdown of FASN in OSCC-MSCs reduced their adipogenic potential and inhibited their ability to promote OSCC cell proliferation and migration. Clinical sample analysis confirmed higher FASN expression in OSCC stroma, correlating with larger tumor size and increased Ki67 expression in cancer tissues, and was associated with poorer overall survival.

OSCC-MSCs promoted OSCC proliferation and migration by upregulating FASN expression and facilitating FFAs secretion. Our results provide new insight into the mechanism of OSCC progression and suggest that the FASN of OSCC-MSCs may be potential targets of OSCC in the future.

Cell microencapsulation is one of the most studied strategies to overcome the challenges associated with the implementation of mesenchymal stem/stromal cells (MSCs) in vivo. This approach isolates/shields donor MSCs from the host immune system using a semipermeable membrane that allows for the diffusion of gases, nutrients, and therapeutics, but not host immune cells. As a result, microencapsulated MSCs survive and engraft better after infusion, and they can be delivered specifically to the targeted site. Additionally, microencapsulation enables the co-culture of MSCs with different types of cells in a three-dimensional (3D) environment, allowing for better cellular interaction. Alginate, collagen, and cellulose are the most popular materials, and air jet extrusion, microfluidics, and emulsion are the most used techniques for MSC cell encapsulation in the literature. These materials and techniques differ in the size range of the resultant microcapsules and their compatibility with the applied materials. This review discusses various materials and techniques used for the microencapsulation of MSCs. We also shed light on the recent findings in this field, the advantages and drawbacks of using encapsulated MSCs, and the in vivo translation of the microencapsulated MSCs in cell therapy.

Indole-3-propionic acid (IPA), a metabolite produced by gut microbiota through tryptophan metabolism, has recently been identified as playing a pivotal role in bone metabolism. IPA promotes osteoblast differentiation by upregulating mitochondrial transcription factor A (Tfam), contributing to increased bone density and supporting bone repair. Simultaneously, it inhibits the formation and activity of osteoclasts, reducing bone resorption, possibly through modulation of the nuclear factor-κB (NF-κB) pathway and downregulation of osteoclast-associated factors, thereby maintaining bone structural integrity. Additionally, IPA provides indirect protection to bone health by regulating host immune responses and inflammation via activation of receptors such as the Aryl hydrocarbon Receptor (AhR) and the Pregnane X Receptor (PXR). This review summarizes the roles and signaling pathways of IPA in bone metabolism and its impact on various bone metabolic disorders. Furthermore, we discuss the therapeutic potential and limitations of IPA in treating bone metabolic diseases, aiming to offer novel strategies for clinical management.

Mesenchymal stromal cells (MSCs) are being tested and accepted as a source for cell therapy worldwide. However, the advanced age of the patients, together with the difficulties in achieving the required cell amounts, impede autologous treatments. Reprogramming of MSCs into induced pluripotent stem cells (iPSCs), followed by re-differentiation to MSCs has emerged as a promising and safe method to facilitate the cell expansion and the removal of aging-associated characteristics. However, the effect of reprogramming on the MSC's pro-angiogenicity is poorly understood.

In this study, we use a microfluidic organ-on-a-chip platform designed for vascularization assays to study and compare the effects of bone marrow MSCs (BM-MSCs) and iPSC-derived MSCs (iMSCs) in stimulating the formation of vessels by endothelial cells. Cells were loaded in fibrin hydrogels, injected into the microfluidic channel, and grown for ten days.

Fluorescence microscopy revealed that BM-MSCs promote the formation of long and interconnected endothelial vessels, while iMSCs barely stimulate neoangiogenesis. This was further confirmed and explained by bulk RNA sequencing, showing a decrease of pro-angiogenic agents in both of the iMSCs co-cultures. Furthermore, transmission electron microscopy revealed that BM-MSCs closely associate with the new vessels as perivascular cells, while iMSCs just remain in proximity.

These results highlight iMSCs as a promising substitute for BM-MSCs in the treatment of diseases with pernicious vascularization, such as osteoarthritis, ocular degeneration, and cancer.

Skeletal stem cells have been isolated from various tissues, including periosteum and bone marrow, where they exhibit key functions in bone biology and hematopoiesis, respectively. The role of periosteal skeletal stem cells in bone regeneration and healing has been extensively studied, but their ability to contribute to the bone marrow stroma is still under debate. In the present study, we characterized a whole bone transplantation model that mimics the initial bone marrow necrosis and fatty infiltration seen after injury. Using this model and a lineage tracing approach, we observed the migration of periosteal skeletal stem cells into the bone marrow after transplantation. Once in the bone marrow, periosteal skeletal stem cells are phenotypically and functionally reprogrammed into bone marrow mesenchymal stem cells that express high levels of hematopoietic stem cell niche factors such as Cxcl12 and Kitl. In addition, using ex vivo and in vivo approaches, we found that periosteal skeletal stem cells are more resistant to acute stress than bone marrow mesenchymal stem cells. These results highlight the plasticity of periosteal skeletal stem cells and their potential role in bone marrow regeneration after bone marrow injury.

LepR-expressing cells (LepR+ cells), a critical subpopulation of mesenchymal stem cells, have gained increasing attention in the last decade. LepR+ cells have been found to play a crucial role in maintaining bone and periodontal homeostasis. This review summarizes current research advances focusing on the role of LepR+ cells and their underlying regulatory molecular mechanisms in bones and periodontium, aiming to provide a better understanding of the therapeutic potential of this cell lineage.

A literature review was conducted based on publications in PubMed over the past 20 years, summarizing the research progress on LepR+ cells in bone and periodontal tissues.

Current evidence revealed that LepR+ cells possess the ability of self-renewal and multilineage differentiation and are essential for bone turnover and periodontal tissue remodeling. In addition, LepR+ cells participate in the processes of bone fracture healing and alveolar socket healing. Moreover, under pathological conditions such as osteoporosis, bone marrow fibrosis, and periodontitis, LepR+ cells exhibit enhanced adipogenic or fibrogenic differentiation abilities.

Therapeutic approaches targeting the cell fate of LepR+ cells hold the potential to provide novel insights into bone/periodontal repair and regeneration therapy.

The mesenchymal stem/stromal cells (MSCs) are multipotent cells that were initially discovered in the bone marrow in the late 1960s but have so far been discovered in almost all tissues of the body. The multipotent property of MSCs enables them to differentiate into various cell types and lineages, such as adipocytes, chondrocytes, and osteocytes. The immunomodulation capacity and tumor-targeting features of MSCs made their use crucial for cell-based therapies in cancer treatment, yet limited advancement could be observed in translational medicine prospects due to the need for more information regarding the controversial roles of MSCs in crosstalk tumors. In this review, we discuss the therapeutic potential of MSCs, the controversial roles played by MSCs in cancer progression, and the anticancer therapeutic strategies that are in association with MSCs. Finally, the clinical trials designed for the direct use of MSCs for cancer therapy or for their use in decreasing the side effects of other cancer therapies are also mentioned in this review to evaluate the current status of MSC-based cancer therapies.

Ischemic stroke is a leading cause of death and disability worldwide, with an increasing trend and tendency for onset at a younger age. China, in particular, bears a high burden of stroke cases. In recent years, the inflammatory response after stroke has become a research hotspot: understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment. This review summarizes several major cells involved in the inflammatory response following ischemic stroke, including microglia, neutrophils, monocytes, lymphocytes, and astrocytes. Additionally, we have also highlighted the recent progress in various treatments for ischemic stroke, particularly in the field of stem cell therapy. Overall, understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes. Stem cell therapy may potentially become an important component of ischemic stroke treatment.

Treatment of complex craniofacial deformities is still a challenge for medicine and dentistry because few approach therapies are available on the market that allow rehabilitation using 3D-printed medical devices. Thus, this study aims to create a scaffold with a morphology that simulates bone tissue, able to create a favorable environment for the development and differentiation of osteogenic cells. Moreover, its association with Plenum Guide, through cell-based tissue engineering (ASCs) for guided bone regeneration in critical rat calvarial defects. The manufacturing and characterization of 3D-printed β-TCP scaffolds for experimental surgery was performed. Nine male rats were divided into three groups: β-TCP + PDO membrane (TCP/PG), β-TCP/ASCs + PDO membrane (TCPasc/PG), and β-TCP/ASCs + PDO membrane/ASCs (TCPasc/PGasc). A surgical defect with a 5-mm diameter was performed in the right parietal bone, and the defect was filled with the 3D-printed β-TCP scaffold and PDO membrane with or without ASCs. The animals were euthanized 7, 14, and 30 days after the surgical procedure for histomorphometric and immunolabeling analyses. 3D-printed β-TCP scaffolds were created with a 404 ± 0.0238 μm gyroid macro-pore and, the association to cell-based therapy promotes, especially in the TCPasc/PGasc group, a bone area formation at the defect border region and the center of the defect. The use of 3D-printed β-TCP scaffolds and PDO membranes associated with cell-based therapy could improve and accelerate guided bone regeneration, promoting an increase in osteogenic capacity and reducing the time involved in the bone formation process. Moreover, using ASCs optimized the bioceramics by increasing its osteoinductive and osteoprogenitor capacity and, even with the resorption of the printed scaffold, aided as a scaffold for mesenchymal cell differentiation, as well as in bone tissue formation.

The present study investigates the influence of nitrosamines and etoposide on mesenchymal stromal cells (MSCs) in a differentiation state- and biological age-dependent manner. The genotoxic effects of the agents on both neonatal and adult stem cell populations after treatment, before, or during the course of differentiation, and the sensitivity of the different MSC types to different concentrations of MNU or etoposide were assessed. Hereby, the multipotent differentiation capacity of MSCs into osteoblasts, adipocytes, and chondrocytes was analyzed. Our findings reveal that while all cell types exhibit DNA damage upon exposure, neonatal CB-USSCs demonstrate enhanced resistance to genotoxic damage compared with their adult counterparts. Moreover, the osteogenic differentiation of MSCs was more susceptible to genotoxic damage, whereas the adipogenic and chondrogenic differentiation potentials did not show any significant changes upon treatment with genotoxin. Furthermore, we emphasize the cell-specific variability in responses to genotoxic damage and the differences in sensitivity and reaction across different cell types, thus advocating the consideration of these variabilities during drug testing and developmental biological research.

Mesenchymal stem cells (MSCs), recognized for their self-renewal and multi-lineage differentiation capabilities, have garnered considerable wide attention since their discovery in bone marrow. Recent studies have underscored the potential of MSCs in immune regulation, particularly in the context of autoimmune diseases, which arise from immune system imbalances and necessitate long-term treatment. Traditional immunosuppressive drugs, while effective, can lead to drug tolerance and adverse effects, including a heightened risk of infections and malignancies. Consequently, adjuvant therapy incorporating MSCs has emerged as a promising new treatment strategy, leveraging their immunomodulatory properties. This paper reviews the immunomodulatory mechanisms of MSCs and their application in autoimmune diseases, highlighting their potential to regulate immune responses and reduce inflammation. The immunomodulatory mechanisms of MSCs are primarily mediated through direct cell contact and paracrine activity with immune cells. This review lays the groundwork for the broader clinical application of MSCs in the future and underscores their significant scientific value and application prospects. Further research is expected to enhance the efficacy and safety of MSCs-based treatments for autoimmune diseases.

Mesenchymal stem cells (MSCs) are widely applied in the treatment of various clinical diseases and in the field of medical aesthetics. However, MSCs exhibit greater heterogeneity limited stability, and more complex molecular and mechanistic characteristics compared to conventional drugs, making rapid and precise monitoring more challenging.

Surface-enhanced Raman spectroscopy (SERS) is an ultrasensitive, tractable and low-cost fingerprinting technique capable of identifying a wide range of molecules related to biological processes. Here, we employed SERS for reproducible quantification of ultralow concentrations of molecules and utilized spectral sets, termed SERSomes, for robust and comprehensive intracellular multi-metabolite profiling.

We revealed that with increasing passage number, there is a gradual decline in cell expansion efficiency, accompanied by significant changes in intracellular amino acids, purines, and pyrimidines. By integrating these metabolic features detected by SERS with transcriptomic data, we established a correlation between SERS signals and biological changes, as well as differentially expressed genes.

In this study, we explore the application of SERS technique to provide robust metabolic characteristics of MSCs across different passages and donors. These results demonstrate the effectiveness of SERSome in reflecting biological characteristics. Due to its sensitivity, adaptability, low cost, and feasibility for miniaturized instrumentation throughout pretreatment, measurement, and analysis, the label-free SERSome technique is suitable for monitoring MSC expansion and offers significant advantages for large-scale MSC manufacturing.

This comprehensive overview of the historical milestones in cell culture underscores key breakthroughs that have shaped the field over time. It begins with Wilhelm Roux's seminal experiments in the 1880s, followed by the pioneering efforts of Ross Granville Harrison, who initiated groundbreaking experiments that fundamentally shaped the landscape of cell culture in the early 20th century. Carrel's influential contributions, notably the immortalization of chicken heart cells, have marked a significant advancement in cell culture techniques. Subsequently, Johannes Holtfreter, Aron Moscona, and Joseph Leighton introduced methodological innovations in three-dimensional (3D) cell culture, initiated by Alexis Carrel, laying the groundwork for future consolidation and expansion of the use of 3D cell culture in different areas of biomedical sciences. The advent of induced pluripotent stem cells by Takahashi and Yamanaka in 2006 was revolutionary, enabling the reprogramming of differentiated cells into a pluripotent state. Since then, recent innovations have included spheroids, organoids, and organ-on-a-chip technologies, aiming to mimic the structure and function of tissues and organs in vitro, pushing the boundaries of biological modeling and disease understanding. In this review, we overview the history of cell culture shedding light on the main discoveries, pitfalls and hurdles that were overcome during the transition from 2D to 3D cell culture techniques. Finally, we discussed the future directions for cell culture research that may accelerate the development of more effective and personalized treatments.

Mesenchymal stem/stromal cells (MSCs), originating from normal tissues, possess the capacity to home to tumor sites and differentiate into tumor-associated MSCs (TA-MSCs), which are instrumental in shaping an immunosuppressive milieu within tumors. Natural killer (NK) cells, integral to the innate immune system, are endowed with the ability to eradicate target cells autonomously, serving as an immediate defense against neoplastic growths. Nonetheless, within the tumor microenvironment (TME), NK cells often exhibit a decline in both their numerical presence and functionality. TA-MSCs have been shown to exert profound inhibitory effects on the functions of tumor-infiltrating immune cells, notably NK cells. Understanding the mechanisms by which TA-MSCs contribute to NK cell dysfunction is critical for the advancement of immune surveillance and the enhancement of tumoricidal responses. This review summarizes existing literature on NK cell modulation by TA-MSCs within the TME and proposes innovative strategies to augment antitumor immunity.

As people's living standards continue to improve and human life span expectancy increases, the incidence and mortality rates of breast cancer are continuously rising. Early detection of breast cancer and targeted therapy for different breast cancer subtypes can significantly reduce the mortality rate and alleviate the suffering of patients. Exosomes are extracellular vesicles secreted by various cells in the body. They participate in physiological and pathological responses by releasing active substances and play an important role in regulating intercellular communication. In recent years, research on exosomes has gradually expanded, and their special membrane structure and targetable characteristics are being increasingly applied in various clinical studies. Mesenchymal stem cells (MSCs)-derived exosomes play an important role in regulating the progression of breast cancer. In this review, we summarize the current treatment methods for breast cancer, the connection between MSCs, exosomes, and breast cancer, as well as the application of exosomes derived from MSCs from different sources in cancer treatment. We highlight how the rational design of modified MSCs-derived exosomes (MSCs-Exos) delivery systems can overcome the uncertainties of stem cell therapy and overcome the clinical translation challenges of nanomaterials. This work aims to promote future research on the application of MSCs-Exos in breast cancer treatment.

Bone tissue provides structural support for our bodies, with the inner bone marrow (BM) acting as a hematopoietic organ. Within the BM tissue, two types of stem cells play crucial roles: mesenchymal stem cells (MSCs) (or skeletal stem cells) and hematopoietic stem cells (HSCs). These stem cells are intricately connected, where BM-MSCs give rise to bone-forming osteoblasts and serve as essential components in the BM microenvironment for sustaining HSCs. Despite the mid-20th century proposal of BM-MSCs, their in vivo identification remained elusive owing to a lack of tools for analyzing stemness, specifically self-renewal and multipotency. To address this challenge, Cre/loxP-based cell lineage tracing analyses are being employed. This technology facilitated the in vivo labeling of specific cells, enabling the tracking of their lineage, determining their stemness, and providing a deeper understanding of the in vivo dynamics governing stem cell populations responsible for maintaining hard tissues. This review delves into cell lineage tracing studies conducted using commonly employed genetically modified mice expressing Cre under the influence of LepR, Gli1, and Axin2 genes. These studies focus on research fields spanning long bones and oral/maxillofacial hard tissues, offering insights into the in vivo dynamics of stem cell populations crucial for hard tissue homeostasis.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease caused by PMP22 duplication and an exceedingly rare hereditary peripheral neuropathy, with an incidence of 1 in 2500. Currently, no cure exists for CMT1A; however, various therapeutic approaches are under development. Considering the known therapeutic effects of mesenchymal stem cells (MSCs) and the relation of blood sugar levels with nerve damage in CMT, this study aimed to confirm the therapeutic effects of MSCs and insulin on CMT, using both in-vitro and in-vivo models. CMT1A in-vitro models were exposed to Wharton's jelly-derived MSCs (WJ-MSCs) or insulin, and the resulting proliferation changes were measured. CMT1A mice were treated with WJ-MSCs or insulin, and their phenotypic changes were observed. We observed improvements in myelination of Schwann cells in vitro and motor function in vivo. Insulin also showed therapeutic efficacy by promoting Schwann cell proliferation. Furthermore, combination therapy using insulin and WJ-MSCs was more effective than WJ-MSCs or insulin alone. Insulin promoted the proliferation of Schwann cells and WJ-MSCs through activation of the ATK and PI3K-MAPK signaling pathways. Overall, this study is the first to confirm the therapeutic efficacy of WJ-MSCs and insulin in CMT1A, and their synergistic effect without causing insulin resistance.

The ever-increasing ageing of the world population is demanding superior orthopedic devices. Issues such as implant infection, poor osseointegration, or chronic inflammation remain problematic to the lifespan and long-term efficacy of implants. Fabrication of materials with bioinspired nanostructures is one emerging antibacterial strategy to prevent implant infection, however their interactions with blood components, and whether they retain their bactericidal properties in an environment displaying a complex protein corona, remains largely unexplored. In the present study, titanium alloy, commercially pure and plasma-sprayed titania were hydrothermally etched, passivated with human native plasma to develop a protein corona, and then incubated with either Staphylococcus aureus, Pseudomonas aeruginosa or human platelets. Surface analysis was first used to characterize the topography, chemical composition or crystallinity of each material. Fluorescence staining and SEM were performed to evaluate the nanostructure bactericidal properties, as well as to study platelet attachment and morphology. Composition of platelet supernatant was studied using ELISA and flow cytometry. Overall, our study showed that the bioinspired nanostructured surfaces displayed both impressive antibacterial properties in a complex environment, and a superior blood biocompatibility profile in terms of platelet activation (particularly for titanium alloy). Additionally, the amount of pro-inflammatory cytokines released by platelets was found to be no different to that found in native plasma (background levels) and, in some cases, presented a more pro-healing profile with an increased secretion of factors such as TGF-β, PDGF-BB or BMP-2. The nanostructured surfaces performed equally, or better, than hydroxyapatite-coated titanium which is one of the current gold standards in orthopedics. Although further in vivo studies are required to validate these results, such bioinspired nanostructured surfaces certainly show promise to be safely applied to medical device surfaces used in orthopedics and other areas.

Mesenchymal stem cells (MSCs) are highly valued in regenerative medicine due to their ability to self-renew and differentiate into various cell types. Their therapeutic benefits are primarily due to their paracrine effects, in particular through extracellular vesicles (EVs), which are related to intercellular communication. Recent advances in EV production and extraction technologies highlight the potential of MSC-derived EVs (MSC-EVs) in tissue engineering and regenerative medicine. MSC-EVs offer several advantages over traditional cell therapies, including reduced toxicity and immunogenicity compared with whole MSCs. EVs carrying functional molecules such as growth factors, cytokines, and miRNAs play beneficial roles in tissue repair, fibrosis treatment, and scar prevention by promoting angiogenesis, skin cell migration, proliferation, extracellular matrix remodeling, and reducing inflammation. Despite the potential of MSC-EVs, there are several limitations to their use, including variability in quality, the need for standardized methods, low yield, and concerns about the composition of EVs and the potential risks. Overall, MSC-EVs are a promising alternative to cell-based therapies, and ongoing studies aim to understand their actions and optimize their use for better clinical outcomes in wound healing and skin regeneration.

Guided tissue regeneration (GTR) has been widely used in the periodontal treatment of intrabony and furcation defects for nearly four decades. The treatment outcomes have shown effectiveness in reducing pocket depth, improving attachment gain and bone filling in periodontal tissue. Although applying GTR could reconstruct the periodontal tissue, the surgical indications are relatively narrow, and some complications and race ethic problems bring new challenges. Therefore, it is challenging to achieve a consensus concerning the clinical benefits of GTR. With the appearance of stem cell-based regenerative medicine, mesenchymal stem/stromal cells (MSCs) have been considered a promising cell resource for periodontal regeneration. In this review, we highlight preclinical and clinical periodontal regeneration using MSCs derived from distinct origins, including non-odontogenic and odontogenic tissues and induced pluripotent stem cells, and discuss the transplantation procedures, therapeutic mechanisms, and concerns to evaluate the effectiveness of MSCs.

Arnold Caplan was the father of MSC, mesenchymal stem cells. His pioneering efforts have led to significant advances in the utilization of mesenchymal stem cells for the treatment of a wide variety of clinical diseases. This reflection provides some insight into Arnold's commitment to education and research regarding mesenchymal stem cells. Moreover, he was a good friend. Arnold will be missed.

Mesenchymal stromal cells (MSCs) showed promising potential for regenerative and therapeutic applications for several pathologies and conditions. Their potential is mainly ascribed to the factors and extracellular vesicles (EVs) they release, which are now envisioned as cell-free therapeutics in cutting-edge clinical studies. A main cornerstone is the preferential uptake by target cells and tissues, in contrast to clearance by phagocytic cells or removal from circulation before reaching the final destination. Recent literature has suggested how the surface properties of EVs might influence their half-life, bio-distribution, and specific uptake. In particular, the concept of a protein corona surrounding EVs emerged. Especially for culture-purified EVs, the process of tailoring a treatment or tissue-specific corona was explored. Liam-Or et al. examined the impact of protein corona on MSC-EVs when specific proteins, preferentially albumin, were adsorbed from media on the EV surface before isolation. This resulted in improved uptake by liver parenchymal cells and reduced incorporation by macrophages, together with an increased half-life in the circulation system. Thus, producing MSC-EVs with an albumin-enriched protein corona might be a camouflage strategy to enhance non-phagocytic uptake in the liver. This research might be a milestone for future studies on other EVs-camouflage approaches tailored to specific tissues and therapeutic applications.

In this editorial we comment on the article by Safwan M et al. We especially focused on the cardiac function restoration by the use of mesenchymal stem cells (MSCs) therapy for heart failure (HF), which has emerged as a new treatment approach as "Living Biodrugs". HF remains a significant clinical challenge due to the heart's inability to pump blood effectively, despite advancements in medical and device-based therapies. MSCs have emerged as a promising therapeutic approach, offering benefits beyond traditional treatments through their ability to modulate inflammation, reduce fibrosis, and promote endogenous tissue regeneration. MSCs can be derived from various tissues, including bone marrow and umbilical cord. Umbilical cord-derived MSCs exhibit superior expansion capabilities, making them an attractive option for HF therapy. Conversely, bone marrow-derived MSCs have been extensively studied for their potential to improve cardiac function but face challenges related to cell retention and delivery. Future research is focusing on optimizing MSC sources, enhancing differentiation and immune modulation, and improving delivery methods to overcome current limitations.