Activated mesenchymal stem/stromal cells promote myeloid cell differentiation via CCL2/CCR2 signaling.

Myeloid cells, which originate from hematopoietic stem/progenitor cells (HSPCs), play a crucial role in mitigating infections. This study aimed to explore the impact of mesenchymal stem/stromal cells (MSCs) on the differentiation of HSPCs and progenitors through the C-C motif chemokine CCL2/CCR2 signaling pathway. Murine MSCs, identified as PDGFRα+Sca-1+ cells (PαS cells), were found to secrete CCL2, particularly in response to lipopolysaccharide stimulation. MSC-secreted CCL2 promoted the differentiation of granulocyte/macrophage progenitors into the myeloid lineage. MSC-derived CCL2 plays an important role in the early phase of myeloid cell differentiation in vivo. Single-cell RNA sequencing analysis confirmed that CCL2-mediated cell fate determination was also observed in human bone marrow cells. These findings provide valuable insights for investigating the in vivo effects of MSC transplantation.

Quality Control of Stem Cell-Based Cultured Meat According to Specific Differentiation Abilities.

The demand for stem cell-based cultured meat as an alternative protein source is increasing in response to global food scarcity. However, the definition of quality controls, including appropriate growth factors and cell characteristics, remains incomplete. Cluster of differentiation (CD) 29 is ubiquitously expressed in bovine muscle tissue and is a marker of progenitor cells in cultured meat. However, CD29+ cells are naturally heterogeneous, and this quality control issue must be resolved. In this study, the aim was to identify the subpopulation of the CD29+ cell population with potential utility in cultured meat production. The CD29+ cell population exhibited heterogeneity, discernible through the CD44 and CD344 markers. CD29+CD44-CD344- cells displayed the ability for long-term culture, demonstrating high adipogenic potential and substantial lipid droplet accumulation, even within 3D cultures. Conversely, CD29+CD44+ cells exhibited rapid proliferation but were not viable for prolonged culture. Using cells suitable for adipocyte and muscle differentiation, we successfully designed meat buds, especially those rich in fat. Collectively, the identification and comprehension of distinct cell populations within bovine tissues contribute to quality control predictions in meat production. They also aid in establishing a stable and reliable cultured meat production technique.

Conservation of Markers and Stemness in Adipose Stem and Progenitor Cells between Cattle and Other Species.

Adipose stem and progenitor cells (ASPCs) have been isolated from humans and animals for use in regenerative medicine and therapy. However, knowledge of ASPCs in other species is limited. Particularly, ASPCs in livestock are expected to enhance the fat content and meat composition. In this study, we isolated bovine ASPCs using cell surface markers. Specifically, we focused on ASPC markers in humans and experimental animals, namely CD26, CD146, and CD54. Stromal vascular fraction cells from bovine fat were separated using flow cytometry before primary culture. We evaluated the self-renewal and adipogenic potential of each fraction. We identified four cell populations: CD26-CD146+CD54+, CD26-CD146+CD54-, CD26-CD146-, and CD26+CD146-. Among them, the CD26-CD146+ fraction, particularly CD54+, demonstrated the properties of preadipocytes (PreAs), characterized by slow proliferation and a high adipogenic capacity. In conclusion, we could collect and characterize possible PreAs as CD26-CD146+CD54+ or CD26-CD146+CD54-, which are expected for in vitro bovine adipogenic assays in the future.

CD73-Positive Cell Spheroid Transplantation Attenuates Colonic Atrophy.

The incidence of inflammatory bowel diseases (IBD) is increasing worldwide. Mesenchymal stem/stromal cells (MSCs) have immunomodulatory functions and are a promising source for cell transplantation therapy for IBD. However, owing to their heterogeneous nature, their therapeutic efficacy in colitis is controversial and depends on the delivery route and form of transplanted cells. Cluster of differentiation (CD) 73 is widely expressed in MSCs and used to obtain a homogeneous MSC population. Herein, we determined the optimal method for MSC transplantation using CD73+ cells in a colitis model. mRNA sequencing analysis showed that CD73+ cells exhibited a downregulation of inflammatory gene expression and an upregulation of extracellular matrix-related gene expression. Furthermore, three-dimensional CD73+ cell spheroids showed enhanced engraftment at the injured site through the enteral route, facilitated extracellular matrix remodeling, and downregulated inflammatory gene expression in fibroblasts, leading to the attenuation of colonic atrophy. Therefore, the interaction between intestinal fibroblasts and exogenous MSCs via tissue remodeling is one mechanism that can be exploited for colitis prevention. Our results highlight that the transplantation of homogeneous cell populations with well-characterized properties is beneficial for IBD treatment.

Risk factors indicating immune-related adverse events with combination chemotherapy with immune checkpoint inhibitors and platinum agents in patients with non-small cell lung cancer: a multicenter retrospective study.

PURPOSE: Immune checkpoint inhibitors (ICI) ushered in a new era for the treatment of non-small cell lung cancer (NSCLC). However, they carry the risk of immune-related adverse events (irAEs). Recently, various studies have been conducted on the predictive factors for irAEs, but there are no reports focusing only on ICI plus platinum agents. The present study aimed to identify the risk factors for irAEs due to ICI combined with platinum-based induction immunochemotherapy in NSCLC patients, focusing only on the period of combined therapy and excluding the period of ICI maintenance therapy. METHODS: This retrospective study included 315 NSCLC patients who started ICI combined with platinum-based chemotherapy treatment at 14 hospitals between December 2018 and March 2021. A logistic regression analysis was used to explore the predictive factors. RESULTS: Fifty patients (15.9%) experienced irAEs. A multivariate analysis revealed that squamous cell carcinoma (P = 0.021; odds ratio [OR]: 2.30; 95% confidence interval [Cl]: 1.14-4.65), anti-programmed death 1 antibody (anti-PD-1) plus anti-cytotoxic T-lymphocyte antigen-4 antibody (anti-CTLA-4) regimens (P < 0.01; OR: 22.10; 95% Cl: 5.60-87.20), and neutrophil-to-lymphocyte rate (NLR) < 3 (P < 0.01; OR: 2.91; 95% Cl: 1.35-6.27) were independent predictive factors for irAEs occurrence. CONCLUSION: Squamous cell carcinoma, anti-PD-1 plus anti-CTLA-4 regimens, and NLR < 3 may be predictive factors for the occurrence of irAEs due to induction immunochemotherapy in patients with NSCLC. By focusing on the potential risk of irAEs in patients with these factors, irAEs can be appropriately managed from an early stage.

Longitudinal Analyses after COVID-19 Recovery or Prolonged Infection Reveal Unique Immunological Signatures after Repeated Vaccinations.

To develop preventive and therapeutic measures against coronavirus disease 2019, the complete characterization of immune response and sustained immune activation following viral infection and vaccination are critical. However, the mechanisms controlling intrapersonal variation in antibody titers against SARS-CoV-2 antigens remain unclear. To gain further insights, we performed a robust molecular and cellular investigation of immune responses in infected, recovered, and vaccinated individuals. We evaluated the serum levels of 29 cytokines and their correlation with neutralizing antibody titer. We investigated memory B-cell response in patients infected with the original SARS-CoV-2 strain or other variants, and in vaccinated individuals. Longitudinal correlation analyses revealed that post-vaccination neutralizing potential was more strongly associated with various serum cytokine levels in recovered patients than in naïve individuals. We found that IL-10, CCL2, CXCL10, and IL-12p40 are candidate biomarkers of serum-neutralizing antibody titer after the vaccination of recovered individuals. We found a similar distribution of virus-specific antibody gene families in triple-vaccinated individuals and a patient with COVID-19 pneumonia for 1 year. Thus, distinct immune responses occur depending on the viral strain and clinical history, suggesting that therapeutic options should be selected on a case-by-case basis. Candidate biomarkers that correlate with repeated vaccination may support the efficacy and safety evaluation systems of mRNA vaccines and lead to the development of novel vaccine strategies.

Isolation and Characterization of Tissue Resident CD29-Positive Progenitor Cells in Livestock to Generate a Three-Dimensional Meat Bud.

The current process of meat production using livestock has significant effects on the global environment, including high emissions of greenhouse gases. In recent years, cultured meat has attracted attention as a way to acquire animal proteins. However, the lack of markers that isolate proliferating cells from bovine tissues and the complex structure of the meat make it difficult to culture meat in a dish. In this study, we screened 246 cell-surface antibodies by fluorescence-activated cell sorting for their capacity to form colonies and their suitability to construct spheroid "meat buds". CD29+ cells (Ha2/5 clone) have a high potency to form colonies and efficiently proliferate on fibronectin-coated dishes. Furthermore, the meat buds created from CD29+ cells could differentiate into muscle and adipose cells in a three-dimensional structure. The meat buds embedded in the collagen gel proliferated in the matrix and formed large aggregates. Approximately 10 trillion cells can theoretically be obtained from 100 g of bovine tissue by culturing and amplifying them using these methods. The CD29+ cell characteristics of bovine tissue provide insights into the production of meat alternatives in vitro.

Growth differentiation factor 6 derived from mesenchymal stem/stromal cells reduces age-related functional deterioration in multiple tissues.

The senescence-associated secretory phenotype (SASP) has attracted attention as a mechanism that connects cellular senescence to tissue dysfunction, and specific SASP factors have been identified as systemic pro-aging factors. However, little is known about the age-dependent changes in the secretory properties of stem cells. Young, but not old, mesenchymal stem/stromal cells (MSCs) are a well-known source of critical regenerative factors, but the identity of these factors remains elusive. In this study, we identified growth differentiation factor 6 (Gdf6; also known as Bmp13 and CDMP-2) as a regenerative factor secreted from young MSCs. The expression of specific secretory factors, including Gdf6, was regulated by the microRNA (miRNA) miR-17, whose expression declined with age. Upregulation of Gdf6 restored the osteogenic capacity of old MSCs in vitro and exerted positive effects in vivo on aging-associated pathologies such as reduced lymphopoiesis, insufficient muscle repair, reduced numbers of neural progenitors in the brain, and chronic inflammation. Our results suggest that manipulation of miRNA could enable control of the SASP, and that regenerative factors derived from certain types of young cells could be used to treat geriatric diseases.

Tropism of cancer stem cells to a specific distant organ.

BACKGROUND: Patients diagnosed with pancreatic cancer have a high mortality rate relating to the highly malignant and refractory nature of their disease, and reputedly linked to the presence of cancerous pancreatic stem cells. These stem cells are believed to be deeply involved in distant metastasis. Therefore, the present study examined whether pancreatic cancer stem cells (CSCs) exhibit organ-specific migration patterns during metastasis. MATERIALS AND METHODS: Pancreatic cancer cells derived from primary tumors isolated from a mouse model of pancreatic cancer were subcutaneously injected into wild-type mice to form tumor allografts. Allografts were isolated and dissociated into single cells prior to cell sorting using flow cytometry. Sorted cancer cells were injected into the tail vein or spleen of recipient wild-type mice, and analyzed for engraftment three weeks post-transplantation. RESULTS: Pancreatic cancer cells metastasized either to the liver or lungs. Furthermore, we compared the number and size of metastatic foci in the liver and lungs; metastatic liver foci were larger compared with those in the lungs. CONCLUSION: Our results showed that pancreatic CSCs metastasize to distinct organs with direct access to the transplantation site via the circulation. Clarifying the interaction between pancreatic CSCs and the liver microenvironment will lead to improved prognosis and treatments for pancreatic cancer.