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LNGFR- and Thy-1-based prospective isolation of human mesenchymal stem cells reveals functionally distinct subpopulations.

ABSTRACT: Human multipotent mesenchymal stem cells (MSCs), isolated based on their adherence to plastic, show poor growth and differentiation and frequently contain contaminating cells, which limits to clarify their own characteristics. In this study, the identification of two cell surface markers, LNGFR and Thy-1, allowed the prospective isolation of highly purified clonogenic human MSCs. Furthermore, single cell sorting assays followed by in vitro expansion revealed three distinct MSC subpopulations: rapidly-, moderately- and slowly proliferating MSC clones (RPCs, MPCs and SPCs, respectively). While RPCs exhibited robust multilineage differentiation and self-renewal potency, MPCs and SPCs contained a majority of senescent cells and exhibited frequent genome errors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE34484 | GEO | 2011/12/22

SECONDARY ACCESSION(S): PRJNA151333

REPOSITORIES: GEO

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Project description:BACKGROUND: Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice.METHODS: hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in 18-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, neuroinflammation, neuroplasticity, endogenous neurogenesis and brain-derived neurotrophic factor (BDNF) were assessed. To determine the mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated.RESULTS: hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of neuroinflammatory responses and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND.CONCLUSIONS: Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.

Project description:Multipotent stromal cells (MSCs) are known for their distinctive ability to differentiate into different cell lineages such as adipocytes, chondrocytes and osteocytes. They can be isolated from numerous tissue sources including bone marrow, adipose tissue, skeletal muscle and others. Because of their differentiation potential and their secretion of growth factors, MSCs are believed to have an inherent quality of regeneration and immune suppression, which are considered advantageous in treating multiple disorders such as graft-versus-host disease. Since the number of MSCs derived from a tissue source is low, cellular expansion is necessary to obtain sufficient numbers for a desired cell therapy. However, after several rounds of passaging, our previous results have shown that MSCs exhibit reduced capacity for proliferation and differentiation. In this study, gene markers of MSC proliferation were identified and evaluated for their ability to predict the cell population proliferative quality. Microarray data of human bone marrow-derived MSCs were correlated with two proliferation assays. A collection of 24 genes were observed to significantly correlate with both proliferation assays (|r| > 0.70) for 8 MSC donors at multiple passages. These 24 identified genes were then confirmed using an additional set of MSCs from 8 new donors using RT-qPCR. The proliferative potential of the second set of MSCs was measured for each donor/passage by three proliferation assays for confluency fraction, fraction of EdU+ cells and population doubling time. The second set of MSCs exhibited a greater proliferative potential at passage 4 in comparison to passage 8, which was distinguishable by 15 genes; however, only 7 of the genes (BIRC5, CCNA2, CDC20, CDK1, PBK, PLK1, SPC25) demonstrated significant correlation (FDR: q < 0.05 and |r| > 0.62) with MSC proliferation regardless of passage. These 7 genes and the proliferative capacity of different non-MSC cell lines were assessed for comparison. Our analyses revealed that correlation between gene expression and proliferation was consistently reduced with the introduction of non-MSC cell lines; therefore this set of 7 genes may be more strongly associated with MSC proliferative quality. These correlative methods may be further used to identify additional markers that exhibit strong correlation with a particular MSC quality such as differentiation or immune suppression potential. Our results pave the way toward the identification of specific gene markers that could rapidly determine the quality of an MSC population for a particular cellular therapy in lieu of an extended in vitro or in vivo assay. Microarray gene expression analysis with confirmation of genes by RT-qPCR

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LNGFR- and Thy-1-based prospective isolation of human mesenchymal stem cells reveals functionally distinct subpopulations.

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