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Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation Potential.

ABSTRACT: Brain perivascular cells have recently been identified as a novel mesodermal cell type in the human brain. These cells reside in the perivascular niche and were shown to have mesodermal and, to a lesser extent, tissue-specific differentiation potential. Mesenchymal stem cells (MSCs) are widely proposed for use in cell therapy in many neurological disorders; therefore, it is of importance to better understand the "intrinsic" MSC population of the human brain. We systematically characterized adult human brain-derived pericytes during in vitro expansion and differentiation and compared these cells with fetal and adult human brain-derived neural stem cells (NSCs) and adult human bone marrow-derived MSCs. We found that adult human brain pericytes, which can be isolated from the hippocampus and from subcortical white matter, are-in contrast to adult human NSCs-easily expandable in monolayer cultures and show many similarities to human bone marrow-derived MSCs both regarding both surface marker expression and after whole transcriptome profile. Human brain pericytes showed a negligible propensity for neuroectodermal differentiation under various differentiation conditions but efficiently generated mesodermal progeny. Consequently, human brain pericytes resemble bone marrow-derived MSCs and might be very interesting for possible autologous and endogenous stem cell-based treatment strategies and cell therapeutic approaches for treating neurological diseases.Perivascular mesenchymal stem cells (MSCs) recently gained significant interest because of their appearance in many tissues including the human brain. MSCs were often reported as being beneficial after transplantation in the central nervous system in different neurological diseases; therefore, adult brain perivascular cells derived from human neural tissue were systematically characterized concerning neural stem cell and MSC marker expression, transcriptomics, and mesodermal and inherent neuroectodermal differentiation potential in vitro and in vivo after in utero transplantation. This study showed the lack of an innate neuronal but high mesodermal differentiation potential. Because of their relationship to mesenchymal stem cells, these adult brain perivascular mesodermal cells are of great interest for possible autologous therapeutic use.

SUBMITTER: Lojewski X

PROVIDER: S-EPMC4572903 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation Potential.

Lojewski Xenia X Srimasorn Sumitra S Rauh Juliane J Francke Silvan S Wobus Manja M Taylor Verdon V Araúzo-Bravo Marcos J MJ Hallmeyer-Elgner Susanne S Kirsch Matthias M Schwarz Sigrid S Schwarz Johannes J Storch Alexander A Hermann Andreas A

Stem cells translational medicine 20150824 10

<h4>Unlabelled</h4>Brain perivascular cells have recently been identified as a novel mesodermal cell type in the human brain. These cells reside in the perivascular niche and were shown to have mesodermal and, to a lesser extent, tissue-specific differentiation potential. Mesenchymal stem cells (MSCs) are widely proposed for use in cell therapy in many neurological disorders; therefore, it is of importance to better understand the "intrinsic" MSC population of the human brain. We systematically ...[more]

PMID: 26304036

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Project description:AimTo compare the phenotypic and neural differentiation potential of human bone marrow derived multipotent adult progenitor cells (MAPC) and mesenchymal stem cells (MSC).MethodsCultures of MAPC and MSC were established in parallel from same samples of human bone marrow (n = 5). Both stem cell types were evaluated for expression of pluripotency markers including Oct-4 and Nanog by immunocytochemistry and reverse-transcription polymerase chain reaction (RT-PCR) and expression of standard mesenchymal markers including CD14, CD34, CD44, CD45, CD73, CD90, CD105 and human leukocyte antigen (HLA)-ABC by flow cytometry. After treatment with neural induction medium both MAPC and MSC were evaluated for expression of neural proteins [neuronal filament-200 (NF-200) and glial fibrillar acidic protein (GFAP)] by immunocytochemistry and Western blotting and neural genes [NF-200, GFAP, Tau, microtubule-associated protein (MAP)-1B, MAP-2, neuron-specific enolase (NSE) and oligodendrocyte-1 (Olig-1)] by quantitative real-time-PCR.ResultsMAPC had small trigonal shaped while MSC had elongated spindle-shaped morphology. The MAPC expressed Oct-4 and Nanog both at gene and protein levels, whereas MSC were negative for these pluripotent markers. MAPC were negative for HLA-ABC while MSC had high expression of HLA-ABC. In addition, MAPC as compared to MSC had significantly lower expression of CD44 (36.56% ± 1.92% vs 98.23% ± 0.51%), CD73 (15.11% ± 2.24% vs 98.53% ± 2.22%) and CD105 (13.81% ± 3.82% vs 95.12% ± 5.65%) (P < 0.001, for all) MAPC cultures compared to MSC cultures treated with neural induction medium had significantly higher fold change expression of NF-200 (0.64), GFAP (0.52), Tau (0.59), MAP-2 (0.72), Olig-1 (0.18) and NSE (0.29) proteins (P < 0.01 for Olig-1 and P < 0.001 for rest) as well as higher fold change expression of genes of NF-200 (1.34), GFAP (1.12), Tau (1.08), MAP-1B (0.92), MAP-2 (1.14) and NSE (0.4) (P < 0.001 for all).ConclusionMAPC can be differentially characterized from MSC as Oct-4 and Nanog positive stem cells with no expression of HLA-ABC and low expression of mesenchymal markers CD44, CD73 and CD105 and when compared to MSC they possess greater predilection for differentiation into neuro-ectodermal lineage.

Project description:Rationale: The groundbreaking discovery of mesenchymal stem cells (MSCs) with their multifaceted benefits led to their widespread application in experimental medicine, including neurology. Efficient delivery of MSCs to damaged regions of the central nervous system may be a critical factor in determining outcome. Integrin VLA-4 (α4β1) coded by ITGA4 and ITGB1 genes is an adhesion molecule expressed by leukocytes, which is responsible for initiation of their diapedesis through cell docking to the inflamed vessel wall expressing VCAM1 receptor. This function of VLA-4 has been recapitulated in neural stem cells and glial progenitors. Thus, it was prudent to investigate this tool as a vehicle driving extravasation of MSCs. Since MSCs naturally express ITGB1 subunit, we decided to supplement them with ITGA4 only. The purpose of our current study is to investigate the eventual fate of IA delivered ITGA4 engineered and naive MSCs. Methods: mRNA-ITGA4 transfected and naive MSCs were injected to right internal carotid artery of rats with focal brain injury. Through next three days MSC presence in animals' brain was navigated by magnetic resonance imaging. Transplanted cell location relative to the brain blood vessels and host immunological reaction were analyzed post-mortem by immunohistochemistry. The chemotaxis of modified and naive MSCs was additionally examined in in vitro transwell migration assay. Results: Both naïve and ITGA4-overexpressing cells remained inside the vascular lumen over the first two days after IA infusion. On the third day, 39% of mRNA-ITGA4 modified and 51% naïve MSCs homed to perivascular space in the injury region (p=NS). The gradual decrease of both naive and mRNA-ITGA4 transfected hBM-MSCs in the rat brain was observed. mRNA-ITGA4 transfected MSCs appeared to be more vulnerable to phagocytosis than naïve cells. Moreover, in vitro study revealed that homogenate from the injured brain repels migration of MSCs, corroborating the incomplete extravasation observed in vivo. Conclusions: In summary, IA transplanted MSCs are capable of homing to the perivascular space, an integral part of neurovascular unit, which might contribute to the replacement of injured pericytes, a critical element facilitating restoration of CNS function. The mRNA-ITGA4 transfection improves cell docking to vessel but this net benefit vanishes over the next two days due to fast clearance from cerebral vessels of the majority of transplanted cells, regardless of their engineering status. The drawbacks of mRNA-ITGA4 transfection become apparent on day 3 post transplantation due to the lower survival and higher vulnerability to host immune attack.

Project description:BackgroundInfant adipose-derived mesenchymal stem cells (ADSCs) collected from excised polydactyly fat tissue, which was surgical waste, could be cultured and expanded in vitro in this study. In addition, the collecting process would not cause pain in the host. In this study, the proliferation, reduction of senescence, anti-oxidative ability, and differentiation potential in the infant ADSCs were compared with those in the adult ADSCs harvested from thigh liposuction to determine the availability of infant ADSCs.MethodsProliferation was determined by detecting the fold changes in cell numbers and doubling time periods. Senescence was analyzed by investigating the age-related gene expression levels and the replicative stress. The superoxide dismutase (SOD) gene expression, adipogenic, neurogenic, osteogenic, and tenogenic differentiation were compared by RT-qPCR. The chondrogenic differentiation efficiency was also determined using RT-qPCR and immunohistochemical staining.ResultsThe proliferation, SOD (SOD1, SOD2 and SOD3) gene expression, the stemness-related gene (c-MYC) and telomerase reverse transcriptase of the infant ADSCs at early passages were enhanced compared with those of the adults'. Cellular senescence related genes, including p16, p21 and p53, and replicative stress were reduced in the infant ADSCs. The adipogenic genes (PPARγ and LPL) and neurogenic genes (MAP2 and NEFH) of the infant ADSC differentiated cells were significantly higher than those of the adults' while the expression of the osteogenic genes (OCN and RUNX) and tenogenic genes (TNC and COL3A1) of both demonstrated opposite results. The chondrogenic markers (SOX9, COL2 and COL10) were enhanced in the infant ADSC differentiated chondrogenic pellets, and the expression levels of SODs were decreased during the differentiation process.ConclusionCultured infant ADSCs demonstrate less cellular senescence and replicative stress, higher proliferation rates, better antioxidant defense activity, and higher potential of chondrogenic, adipogenic and neurogenic differentiation.

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Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation Potential.

Publications

Perivascular Mesenchymal Stem Cells From the Adult Human Brain Harbor No Instrinsic Neuroectodermal but High Mesodermal Differentiation Potential.

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