STEM CELLS最新文献

CD44, a multifunctional cell surface protein, has emerged as a pivotal regulator in cancer stem cell (CSC) biology, orchestrating processes such as stemness, metabolic reprogramming, and therapeutic resistance. Recent studies have identified a critical role of CD44 in ferroptosis resistance by stabilizing SLC7A11 (xCT), a key component of the antioxidant defense system, enabling CSCs to evade oxidative stress and sustain tumorigenic potential. Additionally, CD44 regulates intracellular iron metabolism and redox balance, further supporting CSC survival and adaptation to stressful microenvironments. Therapeutic strategies targeting CD44, including ferroptosis inducers and combination therapies, have shown significant potential in preclinical and early clinical settings. Innovations such as CD44-mediated nanocarriers and metabolic inhibitors present novel opportunities to disrupt CSC-associated resistance mechanisms. Furthermore, the dynamic plasticity of CD44 isoforms governed by transcriptional, post-transcriptional, and epigenetic regulation underscores the importance of context-specific therapeutic approaches. This review highlights the multifaceted roles of CD44 in CSC biology, focusing on its contribution to ferroptosis resistance, iron metabolism, and redox regulation. Targeting CD44 offers a promising avenue for overcoming therapeutic resistance and improving the outcomes of refractory cancers. Future studies are needed to refine these strategies and enable their clinical translation.

Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) that is caused by donor immune cells attacking and damaging host tissues. Immune suppressive small molecule and protein-based therapeutics targeting donor anti-host immune cells are currently used for GVHD prophylaxis and treatment. Even with these therapies, aGVHD progresses to life-threatening steroid-refractory aGVHD (SR-aGVHD) in up to 50% of cases and is a risk factor for the subsequent development of debilitating chronic GVHD. To improve aGVHD-related outcomes, donor graft engineering techniques and adoptive transfer of immune modulatory cells have been explored. Highly rigorous donor graft T-cell depletion approaches have revealed that mitigation of aGVHD can be accompanied by slow immune recovery post-allo-HCT and reduction in anti-microbial and anti-leukemia responses resulting in increased relapse and infection rates, respectively. Recent T-cell separation techniques allowing for precision graft engineering by selectively eliminating aGVHD-causing T-cells (eg, naïve T-cells) without loss of T-cells with beneficial functions and retaining and/or enriching immune regulatory populations (eg, regulatory T-cells (Tregs) or myeloid-derived suppressor cells) have been tested and will continue to improve. Clinical cell-based regulatory therapies have been employed for targeting SR-aGVHD, particularly mesenchymal stem cells (MSCs) and more recently, Tregs. In this review, we summarize aGVHD pathophysiology, highlight newly discovered aGVHD mechanisms, and discuss current and emerging cellular and graft manipulation approaches for aGVHD prevention and treatment.

Transcriptional factor regulation is central to the lineage commitment of stem/ progenitor cells. ZIC1 (ZIC family member 1) is a C2H2-type zinc finger transcription factor expressed during development, brown fat, and certain cancers. Previously, we observed that overexpression of ZIC1 induces osteogenic differentiation at the expense of white adipogenic differentiation. In the present study, the feasibility of ZIC1 overexpressed human progenitor cells in critical-sized bone defects was studied. To achieve this, human adipose stem/stromal cells with other without lentiviral ZIC1 overexpression were implanted in a femoral segmental defect model in NOD-SCIDγ mice. Results showed that ZIC1 overexpressed cells induced osteogenic differentiation by protein markers in a critical-sized femoral segment defect compared to empty lentiviral control, although bone union was not observed. The immunohistochemical evaluation showed that implantation of ZIC1 overexpression cells led to an increase in osteoblast antigen expression (RUNX2, OCN), activation of Hedgehog signaling (Patched1), and an increase in brown adipogenesis markers (ZIC1, EBF2). In contrast, no change in bone defect-associated vasculature was observed (CD31, Endomucin). Together, these data suggest that overexpression of the ZIC1 transcription factor in progenitor cells is associated with differentiation towards osteoblastic and brown adipogenic cell fates.

Inherited bone marrow failure syndromes (IBMFS) are a diverse group of genetic disorders characterized by insufficient hematopoietic cell production due to blood stem cell dysfunction. The most common syndromes are Fanconi Anemia, Diamond-Blackfan Anemia, and Shwachman-Diamond Syndrome. These conditions share a theme of chronically producing pro-inflammatory cytokines such as TNF-α, IL-1β, IL-6, TGF-β, IFN-I, and IFN-γ. Each of these cytokines can impact the bone marrow microenvironment and drive the pathophysiology of IBMFS. This review aims to provide the latest progress in the field regarding the mechanistic underpinnings of inflammation in these IBMFS, as well as the effect of inflammation on the bone marrow microenvironment. A comprehensive understanding of the inflammation in IBMFS will open new avenues for intervention to restore bone marrow stability and improve patient prognosis. Future research must include targeting these mechanisms to develop novel therapies that can potentially mitigate the effects of chronic inflammation in IBMFS.

The C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine ligand 12 (CXCL12), are critical for the homing of hematopoietic stem progenitor cells (HSPCs) to bone marrow (BM). Our previous study revealed that carbohydrate chains on HSPCs are vital in the homing and engraftment of HSPCs. However, the relationship between the glycosylation of CXCR4 and HSPCs homing remains unclear. In this study, we analyzed the glycosylation sites of the N-terminal 38 amino acids of mouse CXCR4, which is indispensable for CXCL12 binding. Among these, simultaneous mutations of possible glycosylation sites, Serine-5 and Serine-9 of mouse CXCR4 lost cell migration activity through CXCL12 in cultured cells and mouse HSPCs. Furthermore, Serine-5 and Serine-9 mutations in HSPCs caused a deficiency in the homing to the BM. Our findings suggest that the glycosylation of mouse CXCR4 is essential for homing HSPCs to the BM, which can be used to screen cord blood HSPCs suitable for transplantation.

Platelet-derived growth factor receptor β (Pdgfrβ) is a cell surface marker often present on mesenchymal progenitor cells, playing a key role in regulating cell proliferation, migration, and survival. In the skeleton, Pdgfrβ-positive cells have significant osteogenic potential, differentiating into osteoblasts after injury to promote bone repair and homeostasis. However, multiple cell types within bone tissue express Pdgfrβ and their overlapping or distinct cellular features remain incompletely understood. Using a combination of single-cell RNA sequencing and transgenic Pdgfrβ-CreERT2-mT/mG reporter mice, we examined Pdgfrβ+ cells in mouse long bone periosteum. By single-cell analysis, Pdgfrb expression was found among a subset of mesenchymal cells and universally among pericytes within the periosteum. Histologic analysis of Pdgfrβ reporter activity confirmed a combination of perivascular and non-perivascular Pdgfrβ-expressing cell types. When isolated, Pdgfrβ reporter+ skeletal periosteal cells showed enhanced colony-forming, proliferative, migratory, and osteogenic capacities. Pdgfrβ reporter+ cells were further distinguished by co-expression of the pericyte marker CD146, which yielded Pdgfrβ+CD146+ pericytes and Pdgfrβ+CD146- skeletal mesenchymal cells. Colony forming and proliferative capacity were most highly enriched among Pdgfrβ+CD146+ pericytes, while osteogenic differentiation was similarly enriched across both Pdgfrβ+ cell fractions. In summary, Pdgfrβ expression identifies multiple subsets of progenitor cells within long bone periosteum with or without perivascular distribution and with overlapping cellular features.

The RUNX1/AML1 transcription factor is one of the key regulators of definitive hematopoietic development in mice. However, its role in early human hematopoiesis remains poorly investigated. In this study, we integrated a tdTomato reporter cassette into the RUNX1 locus of human pluripotent stem cells (hPSCs) to monitor and block the expression of the gene during hPSC differentiation. This approach demonstrated that expression of RUNX1 starts early in mesodermal specification focusing later on hemogenic endothelium (HE) and nascent hematopoietic cells. Lack of RUNX1 halted the development of CD43+ and CD235-CD45+ hematopoietic cells, preventing the production of clonogenic hematopoietic progenitors including the multilineage ones. The abrogation of RUNX1 resulted in the failure of definitive lineages, specifically T and NK cells. Remarkably, we instead observed the accumulation of RUNX1-null HE cells at the stage of blood cell generation. Moreover, the loss of the gene biased the development toward the lineage of CD43-CD146+CD90+CD73+ mesenchymal cells. RNA-seq analysis of RUNX1-null cells revealed the downregulation of top-level hematopoietic transcription factor genes and the reciprocal upregulation of genes associated with non-hematopoietic cells of mesodermal origin. Forced expression of RUNX1c in differentiating RUNX1-null hPSCs effectively rescued the development of CD45+ myeloid cells and megakaryocytes. Our data demonstrate that RUNX1 is a top hematopoietic inducer that simultaneously controls the expansion of non-hematopoietic lineages.

The renin-angiotensin system (RAS) is essential for normal kidney development. Dysregulation of the RAS during embryogenesis can result in kidney abnormalities. To explore how angiotensin type 1 receptor (AT1R) signaling modulates nephron progenitor (NP) fate specification, we used induced pluripotent stem cell (iPSC) derived human kidney organoids treated with angiotensin II (Ang II) or the AT1R blocker losartan during differentiation. Ang II promoted NP proliferation and differentiation preferentially toward a podocyte fate, depleted the podocyte precursor population, and accelerated glomerular maturation. By contrast, losartan expanded the podocyte precursor population, delayed podocyte differentiation, and regressed the transcriptional signature to a more immature fetal state. Overall, using various in silico approaches with validation by RNAscope, we identified a role for AT1R signaling in regulating NP fate during nephrogenesis in kidney organoids. Our work supports the use of RAS modulators to improve organoid maturation and suggests that RAS may be a determinant of nephron endowment in vivo.

Acute kidney injury (AKI) is involved in subsequent chronic kidney disease (CKD) development, and effective treatments to prevent AKI to CKD progression are lacking. Mesenchymal stem cells (MSCs) are emerging as a promising cellular therapy to impede such progression through the secretion of various humoral factors. Among these factors, tumor necrosis factor-α-induced protein 6 (TSG-6) has a central role in the anti-inflammatory effects of MSCs. However, the mechanisms by which MSCs secrete TSG-6 and exert anti-inflammatory effects are not fully clarified. Here, we investigated these mechanisms using TSG-6-overexpressing MSCs (TSG-6 MSCs) with an adeno-associated virus. Extracellular vesicles (EVs) were isolated from MSC culture supernatants by ultracentrifugation. MSCs were injected through the abdominal aorta into rats with ischemia-reperfusion injury (IRI) to evaluate their anti-inflammatory and anti-fibrotic effects. Additionally, we explored natural compounds that increased TSG-6 expression in MSCs. Most TSG-6 was immediately secreted in EVs and was not stored intracellularly. Administration of TSG-6 MSCs strongly suppressed renal fibrosis and inflammation in IRI rats. Although EVs and conditioned medium from TSG-6 MSCs (TSG-6 MSC-CM) strongly promoted polarization of M2 macrophages, TSG-6 MSC-CM after EV depletion promoted it only slightly. Moreover, TSG-6 MSC-CM enhanced regulatory T-cell induction. MSCs treated with indole-3-carbinol had enhanced TSG-6 expression and markedly suppressed IRI-induced renal fibrosis. Taken together, TSG-6 is secreted in EVs from MSCs and exerts potent anti-inflammatory effects by promoting M2 macrophage polarization and regulatory T-cell induction. Administration of MSCs with enhanced TSG-6 secretion is a promising therapeutic strategy to impede AKI to CKD progression.

The human endometrium, a dynamic tissue that undergoes cyclical shedding, repair, regeneration, and remodeling, relies on progenitor stem cells for replenishment. Bone marrow-derived mesenchymal stem cells (BM-MSCs) also may play a crucial role in the physiological process of endometrial regeneration, augmenting endometrial repair, supporting pregnancy, and thereby making a major contribution to reproduction. Notably, defective or inappropriate recruitment and engraftment of stem cells are implicated in various reproductive diseases, including endometriosis, highlighting the potential therapeutic avenues offered by stem cell-targeted interventions. Endometrial progenitor cells have shown promise in improving pregnancy outcomes and addressing infertility issues. Furthermore, BM-MSCs demonstrate the potential to reverse pathologies, including Asherman's syndrome and thin endometrium, offering novel approaches to treating infertility, implantation failure, and recurrent pregnancy loss. Mobilization of endogenous stem cells to areas of pathology through chemoattractants also presents a promising strategy for targeted therapy. Finally, endometrium-derived mesenchymal stem cells, characterized by their multipotent nature and ease of collection through minimally invasive techniques, hold promise in a wide range of reproductive and non-reproductive pathologies, including diabetes, kidney disease, Parkinson's disease, or cardiac disorders. As the best of our knowledge of stem cell biology continues to grow, the incorporation of stem cell-based therapies into clinical practice presents significant potential to transform reproductive medicine and enhance patient outcomes.