Cellular therapies have started an important new therapeutic direction in autistic spectrum disorder (ASD), and the ample diversity of ASD pathophysiology and the different types of cell therapies prompt an equally ample effort to employ clinical studies for studying the ASD causes and cell therapies. Stem cells have yielded so far mixed results in clinical trials, and at patient level the results varied from impressive to no improvement. In this context we have administered autologous cord blood (ACB) and a non-placebo, material intervention represented by an individualized combination of supplements (ICS) to ASD children.

To compare the efficacy of ACB vs ICS and find markers correlated with the child's progress in order to better predict ACB efficacy.

CORDUS clinical study is a crossover study in which both oral ICS and intravenous ACB were sequentially administered to 56 children; ACB was infused as an inpatient procedure. Treatment efficacy was evaluated pre-treatment and post-treatment at 6 months by an independent psychotherapist with Autism Treatment Evaluation Checklist, Quantitative Checklist for Autism in Toddlers and a 16-item comparative table score, after interviewing the children’s parents and therapists. Before and after each intervention participants had a set of blood tests including inflammatory, metabolic and oxidative markers, and the neuronal specific enolase.

No serious adverse reactions were noted during and after cord blood or supplement administration. ACB improved evaluation scores in 78% of children with age 3–7-years (n = 28), but was much less effective in kids older than 8 years or with body weight of more than 35 kg (n = 28; only 11% of children improved scores). ICS yielded better results than ACB in 5 cases out of 28, while in 23 kids ACB brought more improvement than ICS (P < 0.05); high initial levels of inflammation and ferritin were associated with no improvement. Ample individual differences were noted in children's progress, and statistically significant improvements were seen after ACB on areas such as verbalization and social interaction, but not on irritability or aggressive behavior.

ACB has superior efficacy to ICS in ASD; high inflammation, ferritin, age and body weight predict less improvement; more clinical studies are needed for studying ACB efficacy in ASD.

• Autistic spectrum disorder
• Cord blood
• Stem cells
• Neuroinflammation
• Autologous stem cell treatment
• Neuronal specific enolase

• Dental pulp stem cells
• Heterogeneity
• Mesenchymal stromal cells
• NCAM
• Neuronal potential
• P75

• Humans
• Tooth, Deciduous/cytology
• Tooth, Deciduous/metabolism
• Cell Differentiation
• Neurons/cytology
• Neurons/metabolism
• Biomarkers/metabolism
• Cattle
• Mesenchymal Stem Cells/cytology
• Mesenchymal Stem Cells/metabolism
• Animals
• Receptors, Nerve Growth Factor/metabolism
• Cells, Cultured
• CD56 Antigen/metabolism
• Nerve Tissue Proteins/metabolism
• Stem Cells/cytology
• Stem Cells/metabolism
• Child

• advanced therapy medicinal product (ATMP)
• cell therapy
• equipotency
• heterogeneity
• mesenchymal stromal (stem) cell
• pooling

• Cell markers
• Identity
• MSCs
• Mesenchymal stem/stromal cells
• Subpopulation

• Humans
• Mesenchymal Stem Cells/cytology
• Biomarkers/metabolism
• Animals
• Cell Separation/methods

• 2021A1515012484 Basic and Applied Basic Research Foundation of Guangdong Province
• 2023A1515010181 Basic and Applied Basic Research Foundation of Guangdong Province
• 20231120113324002 The fundamental research project of the Shenzhen Science and Technology Innovation Commission

• Cell heterogeneity
• Cytokine priming
• Functional subpopulations
• Mesenchymal stem cells (MSCs)
• Single-cell RNA sequencing (scRNA-seq)

• 2021A1515011108 Basic and Applied Basic Research Foundation of Guangdong Province
• KJZD20230923114504008 Shenzhen Science and Technology Innovation Program

• concentration
• heterogeneity
• mesenchymal stem cells
• phenotype
• tissue source

• L3-3176 Slovenian Research Agency

• bone marrow microenvironment
• clinical applications
• hematopoietic stem cells
• leukemia
• mesenchymal stem cells

• CD317
• Immunosuppression
• MSCs
• Mesenchymal stem/stromal cells
• TSG6

• Humans
• Cell Differentiation
• Mesenchymal Stem Cells
• Cell Proliferation
• Extracellular Matrix
• Anti-Inflammatory Agents/pharmacology
• Mesenchymal Stem Cell Transplantation

• 2021A1515012484 Guangdong Basic and Applied Basic Research Foundation
• 2023A1515010181 Guangdong Basic and Applied Basic Research Foundation

• Animals
• Mice
• Bone Marrow/metabolism
• Chemokines, CXC/metabolism
• Chemokines, CXC/pharmacology
• Chemokines, CXC/therapeutic use
• Cytokines/metabolism
• Imatinib Mesylate/pharmacology
• Imatinib Mesylate/therapeutic use
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
• Neoplastic Stem Cells/metabolism
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Signal Transduction

• Bone marrow mesenchymal stem cells
• CD146+CD271+
• Hematopoietic niche
• Polycythemia vera

• Foreskin mesenchymal stromal cells
• Heterogeneity of immunomodulatory function
• Human umbilical cord mesenchymal stromal cells
• Mesenchymal stromal cells
• Single-cell RNA sequencing

• National Natural Science Foundation of China
• Shenzhen Key Projects of Basic Research
• National Science and Technology Major Project
• Promote Special Projects for Emergency Research for Epidemic Prevention and Control Technology of COVID-19 fund of the Science and Technology Bureau in Dongguan, China
• Science and Technology Projects of Guangdong Province
• Shenzhen Industry and Information Committee "Innovation Chain and Industry Chain" integration special support plan project
• Sanming Project of Medicine in Shenzhen

• CD34
• CD42b glycoproteins
• CD61
• Ki-67 expression
• T cell infiltrations
• apoptosis
• cell cycle
• prostate carcinogenesis

Mesenchymal stem cells (MSCs) are heterogeneous populations with broad application prospects in cell therapy, and using specific subpopulations of MSCs can enhance their particular capability under certain conditions and achieve better therapeutic effects. However, no studies have reported how to obtain high‐quality specific MSC subpopulations in vitro culture. Here, for the first time, we established a general operation process for obtaining high‐quality clinical‐grade cell subpopulations from human umbilical cord MSCs (hUC‐MSCs) based on particular markers. We used the MSC‐CD106⁺ subpopulations, whose biological function has been well documented, as an example to explore and optimize the crucial links of primary preparation, pre‐treatment, antibody incubation, flow sorting, quality and function test. After comprehensively evaluating the quality and function of the acquired MSC‐CD106⁺ subpopulations, including in vitro cell viability, apoptosis, proliferation, marker stability, adhesion ability, migration ability, tubule formation ability, immunomodulatory function and in vivo wound healing ability and proangiogenic activity, we defined an important pre‐treatment scheme which might effectively improve the therapeutic efficiency of MSC‐CD106⁺ subpopulations in two critical clinical application scenarios—direct injection after cell sorting and post‐culture injection into bodies. Based on the above, we tried to establish a general five‐step operation procedure for acquiring high‐quality clinical‐grade MSC subpopulations based on specific markers, which cannot only improve their enrichment efficiency and the reliability of preclinical studies, but also provide valuable methodological guidance for the rapid clinical transformation of specific MSC subpopulations.

Cellular therapy aims to replace damaged resident cells by restoring cellular and molecular environments suitable for tissue repair and regeneration. Among several candidates, mesenchymal stem/stromal cells (MSCs) represent a critical component of stromal niches known to be involved in tissue homeostasis. In vitro, MSCs appear as fibroblast-like plastic adherent cells regardless of the tissue source. The therapeutic value of MSCs is being explored in several conditions, including immunological, inflammatory and degenerative diseases, as well as cancer. An improved understanding of their origin and function would facilitate their clinical use. The stemness of MSCs is still debated and requires further study. Several terms have been used to designate MSCs, although consensual nomenclature has yet to be determined. The presence of distinct markers may facilitate the identification and isolation of specific subpopulations of MSCs. Regarding their therapeutic properties, the mechanisms underlying their immune and trophic effects imply the secretion of various mediators rather than direct cellular contact. These mediators can be packaged in extracellular vesicles, thus paving the way to exploit therapeutic cell-free products derived from MSCs. Of importance, the function of MSCs and their secretome are significantly sensitive to their environment. Several features, such as culture conditions, delivery method, therapeutic dose and the immunobiology of MSCs, may influence their clinical outcomes. In this review, we will summarize recent findings related to MSC properties. We will also discuss the main preclinical and clinical challenges that may influence the therapeutic value of MSCs and discuss some optimization strategies.

• challenges
• clinical value
• mesenchymal stem/stromal cells
• optimization
• therapeutic features

Study of the microenvironment that supports hematopoietic stem cell (HSC) development in vivo is very difficult involving small numbers of interacting cells which are usually not well defined. While much is known about HSC niches located within the bone marrow in terms of contributing cell types and signalling molecules, very little is known about equivalent niches within spleen. Extramedullary hematopoiesis in spleen contributes myeloid cells important in the mobilisation of an immune response. As a result, it is important to develop in vitro models to identify the cells which constitute HSC niches in spleen and to identify the regulatory molecules supporting myeloid cell development. Studies described here document a model system to study the maintenance and differentiation of HSC by splenic stromal cells in vitro. The splenic stromal lines 5G3 and 3B5 differ in hematopoietic support capacity. SVEP1 and IGF2 are molecules of interest specifically expressed by 5G3 stroma. Gene knockdown technology using shRNA plasmids has been used to reduce gene expression in 5G3 and to determine specific effects on myeloid cell development following co-culture with overlaid hematopoietic progenitors in vitro. Knockdown of Svep1 gave specific inhibition of a dendritic cell (DC) population described previously in spleen (L-DC). Knockdown of Igf2 resulted in loss of production of a minor subset of conventional (c) DC. SVEP1 is now considered a marker of mesenchymal stromal cells with osteogenic differentiative capacity reflective of perivascular stromal cells. The power of this in vitro model is evidenced by the fact that it has been used to define SVEP1 as a specific adhesion molecule that regulates the hematopoietic process dependent on stromal niche interaction. The identification of stromal cells and molecules that contribute to the hematopoietic process in spleen, brings us closer to the realm of therapeutically regulating hematopoiesis in vivo, and to inhibiting niches which support cancer stem cells.

• Antibody immobilization
• Cell recruitment
• Chitosan microspheres
• In situ regeneration
• Polydopamine

• bone regeneration
• multipotent stem cells
• pluripotent stem cells

• CD146
• CD34
• adventitial cells
• endometrium
• pericytes
• perivascular stem cells

• Animals
• Cell Differentiation
• Cells, Cultured
• China
• Endometrium
• Endothelial Cells
• Female
• Humans
• Mice
• Stem Cells
• Transplantation, Heterologous

• bone marrow aspirate concentrate
• mesenchymal stromal cells
• single-cell RNA sequencing
• stem cell marker

Mesenchymal stromal cells (MSCs), multipotent progenitors that can be isolated from a variety of different tissues, are becoming increasingly important as cell therapeutics targeting immunopathologies and tissue regeneration. Current protocols for MSC isolation from bone marrow (BM) rely on density gradient centrifugation (DGC), and the production of sufficient MSC doses is a critical factor for conducting clinical MSC trials. Previously, a Good Manufacturing Practice (GMP)–compatible non-woven fabric filter device system to isolate MSCs was developed to increase the MSC yield from the BM. The aim of our study was to compare high-resolution phenotypic and functional characteristics of BM-MSCs isolated with this device and with standard DGC technology.

Human BM samples from 5 donors were analyzed. Each sample was divided equally, processing by DGC, and with the filter device. Stem cell content was assessed by quantification of colony-forming units fibroblasts (CFU-F). Immunophenotype was analyzed by multicolor flow cytometry. In vitro trilineage differentiation potential, trophic factors, and IDO-1 production were assessed. Functionally, immunomodulatory potential, wound healing, and angiogenesis were assayed in vitro.

The CFU-F yield was 15-fold higher in the MSC preparations isolated with the device compared to those isolated by DGC. Consequently, the MSC yield that could be manufactured at passage 3 per mL collected BM was more than 10 times higher in the device group compared to DGC (1.65 × 10⁹ vs. 1.45 × 10⁸). The immunomodulatory potential and IDO-1 production showed donor-to-donor variabilities without differences between fabric filter-isolated and DGC-isolated MSCs. The results from the wound closure assays, the tube formation assays, and the trilineage differentiation assays were similar between the groups with respect to the isolation method. Sixty-four MSC subpopulations could be quantified with CD140a⁺CD119⁺CD146⁺ as most common phenotype group, and CD140a⁺CD119⁺CD146⁺MSCA-1^–CD106^–CD271^– and CD140a⁺CD119⁺CD146^–MSCA-1^–CD106^–CD271^– as most frequent MSC subpopulations. As trophic factors hepatocyte growth factor, epidermal growth factor, brain-derived neurotrophic factor, angiopoietin-1, and vascular endothelial growth factor A could be detected in both groups with considerable variability between donors, but independent of the respective MSC isolation technique.

The isolation of MSCs using a GMP-compatible fabric filter system device resulted in higher yield of CFU-F, producing substantially more MSCs with similar subpopulation composition and functional characteristics as MSCs isolated by DGC.

• GMP
• function
• heterogeneity
• mesenchymal stromal cell
• production
• subpopulation

Granulocyte colony-stimulating factor (G-CSF) was shown to promote bone regeneration and mobilization of vascular and osteogenic progenitor cells. In this study, we investigated the effects of a systemic low dose of G-CSF on both bone consolidation and mobilization of hematopoietic stem/progenitor cells (HSPCs), endothelial progenitor cells (EPCs) and mesenchymal stromal cells (MSCs) in a rat model of distraction osteogenesis (DO). Neovascularization and mineralization were longitudinally monitored using positron emission tomography and planar scintigraphy. Histological analysis was performed and the number of circulating HSPCs, EPCs and MSCs was studied by flow cytometry. Contrary to control group, in the early phase of consolidation, a bony bridge with lower osteoclast activity and a trend of an increase in osteoblast activity were observed in the distracted callus in the G-CSF group, whereas, at the late phase of consolidation, a significantly lower neovascularization was observed. While no difference was observed in the number of circulating EPCs between control and G-CSF groups, the number of MSCs was significantly lower at the end of the latency phase and that of HSPCs was significantly higher 4 days after the bone lengthening. Our results indicate that G-CSF accelerates bone regeneration and modulates mobilization of progenitor cells during DO.

• G-CSF
• bone formation
• endothelial progenitor cells
• hematopoietic stem/progenitor cells
• mesenchymal stromal cells
• neovascularization

• mesenchymal stem cells
• trauma

• 81772319 National Natural Science Foundation of China (National Science Foundation of China)
• 81772319 National Natural Science Foundation of China (National Science Foundation of China)
• 81772319 National Natural Science Foundation of China (National Science Foundation of China)
• 81772319 National Natural Science Foundation of China (National Science Foundation of China)
• 81772319 National Natural Science Foundation of China (National Science Foundation of China)
• 81772319 National Natural Science Foundation of China (National Science Foundation of China)
• 81772319 National Natural Science Foundation of China (National Science Foundation of China)
• 81772319 National Natural Science Foundation of China (National Science Foundation of China)
• National Key R&D Program of China (2019YFA0110600)

• bone
• bone marrow mesenchymal stem cells
• differentiation
• osteoblast

Mesenchymal stem/stromal cells (MSCs) are promising for the treatment of degenerative diseases and traumatic injuries. However, MSC engraftment is not always successful and requires a strong comprehension of the cytokines and their receptors that mediate the biological behaviors of MSCs. The effects of nerve growth factor (NGF) and its two receptors, TrkA and p75NTR, on neural cells are well studied. Increasing evidence shows that NGF, TrkA, and p75NTR are also involved in various aspects of MSC function, including their survival, growth, differentiation, and angiogenesis. The regulatory effect of NGF on MSCs is thought to be achieved mainly through its binding to TrkA. p75NTR, another receptor of NGF, is regarded as a novel surface marker of MSCs. This review provides an overview of advances in understanding the roles of NGF and its receptors in MSCs as well as the effects of MSC‐derived NGF on other cell types, which will provide new insight for the optimization of MSC‐based therapy.

• P75NTR
• TrkA
• cellular therapy
• mesenchymal stem/stromal cell
• nerve growth factor

• Cell identification
• Circulating cells
• HGGVRLY
• Integrin α4β1
• REDV

• Animals
• Antibodies/chemistry
• Antibodies/genetics
• Cell-Derived Microparticles/drug effects
• Fluoresceins/chemistry
• Humans
• Integrin alpha4beta1/chemistry
• Integrin alpha4beta1/genetics
• Ligands
• Oligopeptides/chemistry
• Oligopeptides/genetics
• Peptides/chemistry
• Peptides/genetics
• Peptides/pharmacology
• Protein Binding/drug effects
• Rats

Hair follicle outer root sheath (ORS) is a putative source of stem cells with therapeutic capacity. ORS contains several multipotent stem cell populations, primarily in the distal compartment of the bulge region. However, the bulge is routinely obtained using invasive isolation methods, which require human scalp tissue ex vivo. Non-invasive sampling has been standardized by means of the plucking procedure, enabling to reproducibly obtain the mid-ORS part. The mid-ORS shows potential for giving rise to multiple stem cell populations in vitro. To demonstrate the phenotypic features of distal, middle, and proximal ORS parts, gene and protein expression profiles were studied in physically separated portions. The mid-part of the ORS showed a comparable or higher NGFR, nestin/NES, CD34, CD73, CD44, CD133, CK5, PAX3, MITF, and PMEL expression on both protein and gene levels, when compared to the distal ORS part. Distinct subpopulations of cells exhibiting small and round morphology were characterized with flow cytometry as simultaneously expressing CD73/CD271, CD49f/CD105, nestin, and not CK10. Potentially, these distinct subpopulations can give rise to cultured neuroectodermal and mesenchymal stem cell populations in vitro. In conclusion, the mid part of the ORS holds the potential for yielding multiple stem cells, in particular mesenchymal stem cells.

• hair follicle
• in vitro cultivation
• mesenchymal stem cells
• multipotency
• neuroectodermal cells
• non-invasive sampling
• outer root sheath

• Adult
• Biomarkers/metabolism
• Cell Culture Techniques/methods
• Cell Lineage
• Cell Proliferation
• Cells, Cultured
• Female
• Gene Expression Profiling
• Gene Expression Regulation
• Hair Follicle/cytology
• Humans
• In Vitro Techniques
• Male
• Mesenchymal Stem Cells/cytology
• Stem Cells/cytology

• Mycobacterium tuberculosis
• altruistic stem cells
• bone marrow derived stem cells
• dormancy
• post-primary tuberculosis of the lungs
• reactivation
• stem cell niche

• Bone Marrow Cells/microbiology
• COVID-19
• Humans
• Mesenchymal Stem Cells/microbiology
• Mycobacterium tuberculosis/physiology
• SARS-CoV-2
• Stem Cell Niche/physiology
• Tuberculosis, Pulmonary/microbiology
• Tuberculosis, Pulmonary/transmission
• Virus Activation/physiology
• Virus Latency/physiology

As for many other cancers, the risk of developing hematologic malignancies increases considerably as people age. In recent years, a growing number of studies have highlighted the influence of the aging microenvironment on hematopoiesis and tumor progression. Mesenchymal stromal cells are a major player in intercellular communication inside the bone marrow microenvironment involved in hematopoiesis support. With aging, their functions may be altered, leading to hematopoiesis disturbances which can lead to hematologic cancers. A good understanding of the mechanisms involved in mesenchymal stem cell aging and the consequences on hematopoiesis and tumor progression is therefore necessary for a better comprehension of hematologic malignancies and for the development of therapeutic approaches.

Aging of bone marrow is a complex process that is involved in the development of many diseases, including hematologic cancers. The results obtained in this field of research, year after year, underline the important role of cross-talk between hematopoietic stem cells and their close environment. In bone marrow, mesenchymal stromal cells (MSCs) are a major player in cell-to-cell communication, presenting a wide range of functionalities, sometimes opposite, depending on the environmental conditions. Although these cells are actively studied for their therapeutic properties, their role in tumor progression remains unclear. One of the reasons for this is that the aging of MSCs has a direct impact on their behavior and on hematopoiesis. In addition, tumor progression is accompanied by dynamic remodeling of the bone marrow niche that may interfere with MSC functions. The present review presents the main features of MSC senescence in bone marrow and their implications in hematologic cancer progression.

• aging
• bone marrow niche
• hematologic malignancies
• hematopoiesis
• inflammaging
• inflammation
• mesenchymal stromal cells

The potential use of bone marrow mesenchymal stromal cells (BM-MSCs) for the treatment of osteonecrosis in sickle cell disease (SCD) patients is increasing. However, convenient BM-MSC quantification and functional property assays are critical factors for cell-based therapies yet to be optimized. This study was designed to quantify the MSC population in bone marrow (BM) samples from SCD patients with osteonecrosis (SCD group) and patients with osteoarticular complications not related to SCD (NS group), using flow cytometry for CD271⁺CD45^-/low cell phenotype and CFU-F assay. We also compared expanded BM-MSC osteogenic differentiation, migration, and cytokine secretion potential between these groups. The mean total cell number, CFU-F count, and CD271⁺CD45^-/low cells in BM mononuclear concentrate were significantly higher in SCD than in NS patients. A significant correlation between CD271⁺CD45^-/low cell number and CFU-F counts was found in SCD (r = 0.7483; p = 0.0070) and NS (r = 0.7167; p = 0.0370) BM concentrates. An age-related quantitative reduction of CFU-F counts and CD271⁺CD45^-/low cell number was noted. Furthermore, no significant differences in the morphology, replicative capacity, expression of surface markers, multidifferentiation potential, and secretion of cytokines were found in expanded BM-MSCs from SCD and NS groups after in vitro culturing. Collectively, this work provides important data for the suitable measurement and expansion of BM-MSC in support to advanced cell-based therapies for SCD patients with osteonecrosis.

Salivary gland (SG) hypofunction is a common post-radiotherapy complication. Besides the parenchymal damage after irradiation (IR), there are also effects on mesenchymal stem cells (MSCs) which were shown to contribute to regeneration and repair of damaged tissues by differentiating into stromal cell types or releasing vesicles and soluble factors supporting the healing processes. However, there are no adequate reports about their roles during SG damage and regeneration so far. Using an irradiated SG mouse model, we performed certain immunostainings on tissue sections of submandibular glands at different time points after IR. Immunostaining for CD31 revealed that already one day after IR, vascular impairment was induced at the level of capillaries. In addition, the expression of CD44—a marker of acinar cells—diminished gradually after IR and, by 20 weeks, almost disappeared. In contrast, the number of CD34-positive cells significantly increased 4 weeks after IR and some of the CD34-positive cells were found to reside within the adventitia of arteries and veins. Laser confocal microscopic analyses revealed an accumulation of CD34-positive cells within the area of damaged capillaries where they were in close contact to the CD31-positive endothelial cells. At 4 weeks after IR, a fraction of the CD34-positive cells underwent differentiation into α-SMA-positive cells, which suggests that they may contribute to regeneration of smooth muscle cells and/or pericytes covering the small vessels from the outside. In conclusion, SG-resident CD34-positive cells represent a population of progenitors that could contribute to new vessel formation and/or remodeling of the pre-existing vessels after IR and thus, might be an important player during SG tissue healing.

• Mesenchymal stem cells
• Radiation
• Resident CD34-positive cells
• Salivary gland
• Xerostomia

• CD271+ stem cells
• aphasia treatment
• chronic stroke
• neural stem cells
• spasticity treatment
• stem cell treatment
• stroke treatment

• Adipocytes
• Adipose Tissue
• Humans
• Stem Cells
• Wound Healing

Human periodontal ligament stem cells (hPDLSCs) are a promising source in regenerative medicine. Due to the complexity and heterogeneity of hPDLSCs, it is critical to isolate homogeneous hPDLSCs with high regenerative potential. In this study, p75 neurotrophin receptor (p75NTR) was used to isolate p75NTR⁺ and p75NTR⁻ hPDLSCs by fluorescence‐activated cell sorting. Differences in osteogenic differentiation among p75NTR⁺, p75NTR⁻ and unsorted hPDLSCs were observed. Differential gene expression profiles between p75NTR⁺ and p75NTR⁻ hPDLSCs were analysed by RNA sequencing. α1 Integrin (ITGA1) small interfering RNA and ITGA1‐overexpressing adenovirus were used to transfect p75NTR⁺ and p75NTR⁻ hPDLSCs. The results showed that p75NTR⁺ hPDLSCs demonstrated superior osteogenic capacity than p75NTR⁻ and unsorted hPDLSCs. Differentially expressed genes between p75NTR⁺ and p75NTR⁻ hPDLSCs were highly involved in the extracellular matrix‐receptor interaction signalling pathway, and p75NTR⁺ hPDLSCs expressed higher ITGA1 levels than p75NTR⁻ hPDLSCs. ITGA1 silencing inhibited the osteogenic differentiation of p75NTR⁺ hPDLSCs, while ITGA1 overexpression enhanced the osteogenic differentiation of p75NTR⁻ hPDLSCs. These findings indicate that p75NTR optimizes the osteogenic potential of hPDLSCs by up‐regulating ITGA1 expression, suggesting that p75NTR can be used as a novel cell surface marker to identify and purify hPDLSCs to promote their applications in regenerative medicine.

• cell surface marker
• human periodontal ligament stem cells
• osteogenic differentiation
• regenerative medicine
• signalling pathway

• Bone Marrow Niche
• Endocannabinoids
• Hematopoiesis
• Neuropeptides
• Opioids
• Tachykinins

Mesenchymal stromal cells (MSCs) possess several fairly unique properties that, when combined, make them ideally suited for cellular-based immunotherapy and as vehicles for gene and drug delivery for a wide range of diseases and disorders. Key among these are: (1) their relative ease of isolation from a variety of tissues; (2) the ability to be expanded in culture without a loss of functionality, a property that varies to some degree with tissue source; (3) they are relatively immune-inert, perhaps obviating the need for precise donor/recipient matching; (4) they possess potent immunomodulatory functions that can be tailored by so-called licensing in vitro and in vivo; (5) the efficiency with which they can be modified with viral-based vectors; and (6) their almost uncanny ability to selectively home to damaged tissues, tumors, and metastases following systemic administration. In this review, we summarize the latest research in the immunological properties of MSCs, their use as immunomodulatory/anti-inflammatory agents, methods for licensing MSCs to customize their immunological profile, and their use as vehicles for transferring both therapeutic genes in genetic disease and drugs and genes designed to destroy tumor cells.

• bone marrow niche
• ex-vivo gene therapy
• hematopoietic stem and progenitor cells
• hematopoietic stem cell transplantation
• mesenchymal stromal cells

• bone healing
• inflammation
• regeneration
• senescence
• skeletal stem cell

• bone marrow-derived mesenchymal stem cells
• cartilage
• cell separation
• hydrogel
• mesenchymal stromal cells
• point of care

In the current study we compared the molecular signature of expanded mesenchymal stromal cells (MSCs) derived from selected CD271+ bone marrow mononuclear cells (CD271-MSCs) and MSCs derived from non-selected bone marrow mononuclear cells by plastic adherence (PA-MSCs). Transcriptome analysis demonstrated for the first time the upregulation of 115 and downregulation of 131 genes in CD271-MSCs. Functional enrichment analysis showed that the upregulated genes in CD271-MSCs are significantly enriched for extracellular matrix (tenascin XB, elastin, ABI family, member 3 (NESH) binding protein, carboxypeptidase Z, laminin alpha 2 and nephroblastoma overexpressed) and cell adhesion (CXCR7, GPNMB, MYBPH, SVEP1, ARHGAP6, TSPEAR, PIK3CG, ABL2 and NCAM1). CD271-MSCs expressed higher gene transcript levels that are involved in early osteogenesis/chondrogenesis/adipogenesis (ZNF145, FKBP5). In addition, increased transcript levels for early and late osteogenesis (DPT, OMD, ID4, CRYAB, SORT1), adipogenesis (CTNNB1, ZEB, LPL, FABP4, PDK4, ACDC), and chondrogenesis (CCN3/NOV, CCN4/WISP1, CCN5/WISP2 and ADAMTS-5) were detected. Interestingly, CD271-MSCs expressed increased levels of hematopoiesis associated genes (CXCL12, FLT3L, IL-3, TPO, KITL). Down-regulated genes in CD271-MSCs were associated with WNT and TGF-beta signaling, and cytokine/chemokine signaling pathways. In addition to their capacity to support hematopoiesis, these results suggest that CD271-MSCs may contain more osteo/chondro progenitors and/or feature a greater differentiation potential.

• Early brain injury
• chemokine receptor 2
• p75 neurotrophin receptor
• resident microglia
• subarachnoid hemorrhage

• Animals
• Brain Injuries/etiology
• Brain Injuries/metabolism
• Brain Injuries/prevention & control
• Female
• Gene Products, tat/pharmacology
• Gene Products, tat/therapeutic use
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Microglia/drug effects
• Microglia/metabolism
• Monocytes/drug effects
• Monocytes/metabolism
• Neuroprotective Agents/pharmacology
• Neuroprotective Agents/therapeutic use
• Random Allocation
• Receptors, Nerve Growth Factor/antagonists & inhibitors
• Receptors, Nerve Growth Factor/metabolism
• Subarachnoid Hemorrhage/complications
• Subarachnoid Hemorrhage/drug therapy
• Subarachnoid Hemorrhage/metabolism

Mesenchymal stromal cells (MSCs) are key elements in the bone marrow (BM) niche where they interact with hematopoietic stem progenitor cells (HSPCs) by offering physical support and secreting soluble factors, which control HSPC maintenance and fate. Although necessary for their maintenance, MSCs are a rare population in the BM, they are plastic adherent and can be ex vivo expanded to reach numbers adequate for clinical use. In light of HSPC supportive properties, MSCs have been employed in phase I/II clinical trials of hematopoietic stem cell transplantation (HSCT) to facilitate engraftment of hematopoietic stem cells (HSCs). Moreover, they have been utilized to expand ex vivo HSCs before clinical use. The available clinical evidence from these trials indicate that MSC administration is safe, as no acute and long-term adverse events have been registered in treated patients, and may be efficacious in promoting hematopoietic engraftment after HSCT. In this review, we critically discuss the role of MSCs as component of the BM niche, as recent advances in defining different mesenchymal populations in the BM have considerably increased our understanding of this complex environment. Moreover, we will revise published literature on the use of MSCs to support HSC engraftment and expansion, as well as consider potential new MSC application in the clinical context of ex vivo gene therapy with autologous HSC.