Stem Cells

Cytochrome P450 3A4 (CYP3A4) is involved in first-pass metabolism in the small intestine and is heavily implicated in oral drug bioavailability and pharmacokinetics. We previously reported that Vitamin D3 (VD3), a known CYP enzyme inducer, induces functional maturation of iPSC-derived enterocyte-like cells (iPSC-ent). Here, we identified a Notch activator and CYP modulator Valproic Acid (VPA), as a promotor for the maturation of iPSC-ent. We performed bulk RNA sequencing to investigate the changes in gene expression during the differentiation and maturation periods of these cells...

Several differentiation protocols enable the emergence of hematopoietic stem and progenitor cells (HSPCs) from human induced pluripotent stem cells (iPSCs), yet optimized schemes to promote the development of HSPCs with self-renewal, multilineage differentiation and engraftment potential are lacking. To improve human iPSC differentiation methods, we modulated WNT, Activin/Nodal and MAPK signaling pathways by stage-specific addition of small molecule regulators CHIR99021, SB431542 and LY294002, respectively, and measured the impact on hematoendothelial formation in culture...

Enhanced adipogenic differentiation of mesenchymal stem cells (MSCs) is considered as a major risk factor of steroid-induced osteonecrosis of the femoral head (SOFNH). The role of microRNAs during this process has sparked interest. miR-486-5p expression was down-regulated significantly in femoral head bone tissues of both SONFH patients and rat model. The purpose of this study was to reveal the role of miR-486-5p on MSCs adipogenesis and SONFH progression. The present study showed that miR-486-5p could significantly inhibit adipogenesis of 3T3-L1 cells by suppressing mitotic clonal expansion (MCE)...

Myocardial infarction (MI) is a serious threat to human health. Although monotherapy with pulsed electromagnetic fields (PEMFs) or adipose-derived stem cells (ADSCs) has been reported to have positive effect on the treatment of MI, a satisfactory outcome has not yet been achieved. In recent years, combination therapy has attracted widespread interest. Herein, we explored the synergistic therapeutic effect of combination therapy with PEMFs and ADSCs on MI and found that the combination of PEMFs and ADSCs effectively reduced infarct size, inhibited cardiomyocyte apoptosis and protected the cardiac function in mice with MI...

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Bone marrow mesenchymal stem cells (BMSCs) are indispensable cells constituting the bone marrow microenvironment that are generally recognized as being involved in the development and progression of osteosarcoma (OS). To explore whether mTORC2 signaling inhibition in BMSCs suppressed OS growth and tumor-caused bone destruction, 3-month-old littermates genotyped Rictor flox/flox or Prx1-cre; Rictor flox/flox (with same gender) were injected with K7M2 cells in the proximal tibia. After 40 days, bone destruction was alleviated in Prx1-cre; Rictor flox/flox mice, as observed on X-ray and micro-CT...

After ischemia, cells in the brain parenchyma upregulate stromal derived factor 1 (SDF1), driving chemokine receptor CXCR4-mediated migration of adult neural stem cells to the ischemic injury. We discovered a novel regulator of CXCR4 in neural stem cells, low-density lipoprotein receptor related protein 1 (LRP1). We employed Nestin-driven knockout of LRP1 and induction of td-tomato in neural stem cells of adult mice. We observed reduced localization of td-tomato positive cells to the lesion, and find disrupted CXCR4-mediated neural stem cell migration in vitro, which is likely driven by LRP1-mediated loss of CXCR4 expression in vivo...

Articular cartilage has a limited capacity for self-repair and clinical approaches to cartilage regeneration are needed. The only such approach developed to date involves an expansion of primary autologous chondrocytes in culture, followed by their reimplantation into a cartilage defect. However, because of the formation of fibrocartilage instead of hyaline cartilage, the outcome is often not satisfactory. It happens due to the de-differentiation of chondrocytes during the expansion step. Indeed, articular chondrocytes are non-proliferative and require partial or complete dedifferentiation before actively proliferating...

During early embryogenesis, the transcription factor SOX17 contributes to hepato-pancreato-biliary system formation and vascular-hematopoietic emergence. To better understand Sox17 function in the developing endoderm and endothelium, we developed a dual-color temporal lineage-tracing strategy in mice combined with single-cell RNA sequencing to analyze 6,934 cells from Sox17-expressing lineages at embryonic day 9.0-9.5. Our analyses showed 19 distinct cellular clusters combined from all three germ layers. Differential gene expression, trajectory and RNA-velocity analyses of endothelial cells revealed a heterogenous population of uncommitted and specialized endothelial subtypes, including two hemogenic populations that arise from different origins...

Achilles tendon rupture is a common sports-related injury. Even with advanced clinical treatments, many patients suffer from long-term pain and functional deficits. These unsatisfactory outcomes result primarily from an imbalanced injury response with excessive inflammation and inadequate tendon regeneration. Prior studies showed that extracellular vesicles from inflammation-primed adipose-derived stem cells (iEVs) can attenuate early tendon inflammatory response to injury. It remains to be determined if iEVs can both reduce inflammation and promote regeneration in the later phases of tendon healing and the underlying mechanism...

In mammals, post-injury repair and regenerative events rely predominantly on stem cell function. Stem cell transplantation has achieved considerable success in animals but remains unfavorable for humans because of the unavoidable drawbacks. Nevertheless, substantial evidence suggests the regenerative potential of endogenous stem cells can be improved for functional and structural recovery of tissue damage or in diseases conditions. Endogenous stem cells are mostly quiescent under steady-state conditions and reside in their niche...

Corneal alkali burns cause extensive damage not only on the cornea but also into the intraocular tissues. As an anti-inflammatory therapy, subconjunctival administration of mesenchymal stem cells (MSCs) for corneal protection after corneal alkali burn has been explored. Little evidence demonstrates the potential of subconjunctival MSCs delivery in protecting the post-burn intraocular tissues. This study aimed to evaluate the therapeutic efficacy of subconjunctival injection of human placental (hP)-MSCs in protecting against ocular destruction after the burn...

The limited availability of organs for liver transplantation, the ultimate curative treatment for end stage liver disease, has resulted in a growing and unmet need for alternative therapies. Mesenchymal stromal cells with their broad ranging anti-inflammatory and immunomodulatory properties have therefore emerged as a promising therapeutic agent in treating inflammatory liver disease. Significant strides have been made in exploring their biological activity. Clinical application of MSC has shifted the paradigm from using their regenerative potential to one which harnesses their immunomodulatory properties...

Despite developing neurosurgical procedures, few treatment options have achieved functional recovery from traumatic brain injury (TBI). Neural stem/progenitor cells (NS/PCs) may produce a long-term effect on neurological recovery. Although induced pluripotent stem cells (iPSCs) can overcome ethical and practical issues of human embryonic or fetal-derived tissues in clinical applications, the tumorigenicity of iPSC-derived populations remains an obstacle to their safe use in regenerative medicine. We herein established a novel treatment strategy for TBI using iPSCs expressing the enzyme-prodrug gene yeast cytosine deaminase-uracil phosphoribosyl transferase (yCD-UPRT)...

Diamond Blackfan Anemia (DBA) is an inherited bone marrow failure syndrome associated with severe anemia, congenital malformations and increased risk of developing cancer. The chromatin-binding SATB1 is downregulated in Megakaryocyte/Erythroid Progenitors (MEPs) in patients and cell models of DBA, leading to a reduction in MEP expansion. Here we demonstrate that SATB1 expression is required for the upregulation of the critical erythroid factors HSP70 and GATA1 that accompanies MEP differentiation. SATB1 binding to specific sites surrounding the HSP70 genes, promotes chromatin loops that are required for induction of HSP70, which in turn promotes GATA1 induction...

Migration of mesenchymal stem cells (MSCs) to the site of injury is crucial in transplantation therapy. Studies have shown that cell migration is regulated by the cellular microenvironment and accompanied by changes in cellular metabolism. However, limited information is available about the relationship between MSC migration and cellular metabolism. Here, we show that basic fibroblast growth factor (bFGF) promotes the migration of MSCs with high levels of glycolysis and high expression of hexokinase 2 (HK2), a rate-limiting enzyme in glycolysis...

Epigenetic mechanisms regulate the multilineage differentiation capacity of hematopoietic stem cells (HSCs) into a variety of blood and immune cells. Mapping the chromatin dynamics of functionally defined cell populations will shed mechanistic insight on two major, unanswered questions in stem cell biology: how does epigenetic identity contribute to a cell type's lineage potential, and how do cascades of chromatin remodeling dictate ensuing fate decisions? Our recent work revealed evidence of multilineage gene priming in HSCs, where open cis-regulatory elements (CREs) exclusively shared between HSCs and unipotent lineage cells were enriched for DNA binding motifs of known lineage-specific transcription factors...

For adipose stromal/stem cell (ASCs)-based immunomodulatory therapies, it is important to study how donor characteristics, such as obesity and type 2 diabetes (T2D), influence ASCs efficacy. Here, ASCs were obtained from two groups, donors and T2D and obesity (dASCs) or nondiabetic donors with normal-weight (ndASCs), and then cultured with anti-CD3/CD28-stimulated allogeneic CD4 T cells. ASCs were studied for the expression of the immunomodulators CD54, CD274, and indoleamine 2, 3 dioxygenase 1 (IDO) in inflammatory conditions...

Skeletal muscle is mainly composed of multinucleated cells called myofibers, and has excellent regenerative and adaptive abilities. These abilities are granted by muscle satellite cells (MuSCs), which are anatomically defined cells located between myofibers and basal lamina. In addition to myofibers and MuSCs, skeletal muscle contains several types of cells located in interstitial areas, such as mesenchymal progenitors. These cells are positive for platelet-derived growth factor receptor alpha and are called fibro/adipogenic progenitors (FAPs) or mesenchymal stromal cells...

Mesenchymal stem/stromal cell (MSC)-based therapies have been evaluated in over 1500 human clinical trials for a diverse array of disease indication, but outcomes remain unpredictable due to knowledge gaps in the quality attributes that confer therapeutic potency onto cells and their mode of action in vivo. Based on accumulated evidence from pre-clinical models, MSCs exert therapeutic effects by repressing inflammatory and immune-mediated response via paracrine action following reprogramming by the host injury microenvironment, and by polarization of tissue resident macrophages following phagocytosis to an alternatively activated (M2) state...