Abstract:The effect of transplantation dose on the spatiotemporal dynamics of human neural stem cell engraftment has not been quantitatively evaluated in the central nervous system. We investigated changes over time in engraftment/survival, proliferation, and migration of multipotent human central nervous system-derived neural stem cells (hCNS-SCns) transplanted at doses ranging from 10,000 to 500,000 cells in spinal cord injured immunodeficient mice. Transplant dose was inversely correlated with measures of donor cell… Show more
“…A significant positive correlation was observed between transplant dose and number of human cells in the SCI microenvironment (Figure 1C), suggesting a linear relationship between these factors. However, there was a significant improvement in goodness of fit when a second-order polynomial was applied to the dataset containing all dose groups ( r 2 = 0.7, p ≤ 0.02 versus r 2 = 0.6, p ≤ 0.8), which was not apparent when the very-high-dose group was eliminated from the dataset; ( r 2 = 0.7, p ≤ 1.0), suggesting a plateau of donor cell engraftment at the highest (500,000 cells) transplant dose (Piltti et al., 2015). This change was not related to differences in either cell death, as assessed by cleaved CASP3, or proliferation, as assessed by SC121 + /MKI67 + human cells, as no significant differences were observed in these measures between groups (Piltti et al., 2015).…”
Section: Resultsmentioning
confidence: 99%
“…However, there was a significant improvement in goodness of fit when a second-order polynomial was applied to the dataset containing all dose groups ( r 2 = 0.7, p ≤ 0.02 versus r 2 = 0.6, p ≤ 0.8), which was not apparent when the very-high-dose group was eliminated from the dataset; ( r 2 = 0.7, p ≤ 1.0), suggesting a plateau of donor cell engraftment at the highest (500,000 cells) transplant dose (Piltti et al., 2015). This change was not related to differences in either cell death, as assessed by cleaved CASP3, or proliferation, as assessed by SC121 + /MKI67 + human cells, as no significant differences were observed in these measures between groups (Piltti et al., 2015). Figure 1Transplantation of hCNS-SCns in Early Chronic SCI, at 30 dpi, Results in a Linear Increase in Engraftment that Is Positively Correlated with Initial Transplantation Dose(A) Representative coronal spinal cord sections immunostained for SC121 (STEM121) and hematoxylin 16 WPT.…”
Section: Resultsmentioning
confidence: 99%
“…Analysis of total human cell number in each quantified section (Figure S4) revealed that hCNS-SCns in all dose groups exhibited extensive migration. Human cells were localized up to 7 mm rostral and caudal to the transplantation sites and injury epicenter, with no significant differences between groups (Figures 5 and S4; Piltti et al., 2015). However, the low-dose group exhibited a significantly greater proportion of total SC121 + , OLIG2 + oligodendroglial, and DCX + early neuronal human cells in the region rostral and proximal to the epicenter (Figures 5B–5E).…”
SummaryMultipotent human central nervous system-derived neural stem cells transplanted at doses ranging from 10,000 (low) to 500,000 (very high) cells differentiated predominantly into the oligodendroglial lineage. However, while the number of engrafted cells increased linearly in relationship to increasing dose, the proportion of oligodendrocytic cells declined. Increasing dose resulted in a plateau of engraftment, enhanced neuronal differentiation, and increased distal migration caudal to the transplantation sites. Dose had no effect on terminal sensory recovery or open-field locomotor scores. However, total human cell number and decreased oligodendroglial proportion were correlated with hindlimb girdle coupling errors. Conversely, greater oligodendroglial proportion was correlated with increased Ab step pattern, decreased swing speed, and increased paw intensity, consistent with improved recovery. These data suggest that transplant dose, and/or target niche parameters can regulate donor cell engraftment, differentiation/maturation, and lineage-specific migration profiles.
“…A significant positive correlation was observed between transplant dose and number of human cells in the SCI microenvironment (Figure 1C), suggesting a linear relationship between these factors. However, there was a significant improvement in goodness of fit when a second-order polynomial was applied to the dataset containing all dose groups ( r 2 = 0.7, p ≤ 0.02 versus r 2 = 0.6, p ≤ 0.8), which was not apparent when the very-high-dose group was eliminated from the dataset; ( r 2 = 0.7, p ≤ 1.0), suggesting a plateau of donor cell engraftment at the highest (500,000 cells) transplant dose (Piltti et al., 2015). This change was not related to differences in either cell death, as assessed by cleaved CASP3, or proliferation, as assessed by SC121 + /MKI67 + human cells, as no significant differences were observed in these measures between groups (Piltti et al., 2015).…”
Section: Resultsmentioning
confidence: 99%
“…However, there was a significant improvement in goodness of fit when a second-order polynomial was applied to the dataset containing all dose groups ( r 2 = 0.7, p ≤ 0.02 versus r 2 = 0.6, p ≤ 0.8), which was not apparent when the very-high-dose group was eliminated from the dataset; ( r 2 = 0.7, p ≤ 1.0), suggesting a plateau of donor cell engraftment at the highest (500,000 cells) transplant dose (Piltti et al., 2015). This change was not related to differences in either cell death, as assessed by cleaved CASP3, or proliferation, as assessed by SC121 + /MKI67 + human cells, as no significant differences were observed in these measures between groups (Piltti et al., 2015). Figure 1Transplantation of hCNS-SCns in Early Chronic SCI, at 30 dpi, Results in a Linear Increase in Engraftment that Is Positively Correlated with Initial Transplantation Dose(A) Representative coronal spinal cord sections immunostained for SC121 (STEM121) and hematoxylin 16 WPT.…”
Section: Resultsmentioning
confidence: 99%
“…Analysis of total human cell number in each quantified section (Figure S4) revealed that hCNS-SCns in all dose groups exhibited extensive migration. Human cells were localized up to 7 mm rostral and caudal to the transplantation sites and injury epicenter, with no significant differences between groups (Figures 5 and S4; Piltti et al., 2015). However, the low-dose group exhibited a significantly greater proportion of total SC121 + , OLIG2 + oligodendroglial, and DCX + early neuronal human cells in the region rostral and proximal to the epicenter (Figures 5B–5E).…”
SummaryMultipotent human central nervous system-derived neural stem cells transplanted at doses ranging from 10,000 (low) to 500,000 (very high) cells differentiated predominantly into the oligodendroglial lineage. However, while the number of engrafted cells increased linearly in relationship to increasing dose, the proportion of oligodendrocytic cells declined. Increasing dose resulted in a plateau of engraftment, enhanced neuronal differentiation, and increased distal migration caudal to the transplantation sites. Dose had no effect on terminal sensory recovery or open-field locomotor scores. However, total human cell number and decreased oligodendroglial proportion were correlated with hindlimb girdle coupling errors. Conversely, greater oligodendroglial proportion was correlated with increased Ab step pattern, decreased swing speed, and increased paw intensity, consistent with improved recovery. These data suggest that transplant dose, and/or target niche parameters can regulate donor cell engraftment, differentiation/maturation, and lineage-specific migration profiles.
“…As in the field of stroke, although a variety of benefits have been reported, integration with the host has not been demonstrated. Also unresolved are the questions of optimal dosing and dose scaling to man; this is a tricky issue because, at least based on our experience on spinal cord injury, dose escalation alters the dynamics of engraftment, migration, and fate (19). Even less can be said about stem cell therapies for models of DAI, although the field can borrow from spinal cord injury that invariably involves trauma in axonal tracts.…”
Section: Special Considerations For Focal Tbi and Daimentioning
“…A considerable amount of studies demonstrated that NSCs could repair the damage of central or peripheral nervous system. [10][11][12][13][14] However, transplantation of NSCs has shortcomings: the survival rate of NSCs is low; 15 most NSCs differentiate into astrocytes; and cavities are observed to exist after NSCs transplantation. 10,11,16,17 Another important factor in tissue engineering is growth factors.…”
Background:To investigate the biocompatibility of electrospinning polycaprolactone (PCL) fiber scaffolds and coculture system, which consisted of neural stem cells (NSCs) and activated Schwann cells (ASCs). Materials and methods: ASCs were isolated from sciatic nerves, ligated for 7 days, in 4-week-old Wistar rats, and the NSCs were isolated from the hippocampus of E14.5 Wistar rat embryos. ASCs, NSCs and ASCs combined with NSCs were 3D cultured on the electrospinning PCL fiber scaffolds. Crystal violet staining was used to find the suitable density of ASCs for growth, and the proliferation of NSCs and ASCs were tested by Cell Counting Kit (CCK)-8 assay, and cell adhesion, differentiation of NSCs and myelin basic protein (MBP) expression of ASCs were observed by laser confocal microscopy. Distribution and morphology were assessed by scanning electron microscopy. Results: The average diameter of fibers in electrospinning PCL scaffolds was approximately 7.93±1.41 μm. ASCs could grow well at the density of 2×10 4 /cm 2 , and a certain number of cells extended along the longitudinal axis of fibers, and the shape of the cells was spindle, which was consistent with crystal violet staining results. The CCK-8 experiment showed ASCs could proliferate gradually on the PCL scaffold within 7 days, as well as NSCs, and NSCs differentiated into astrocytes, neurons and oligodendrocytes on the PCL scaffold; PCL scaffolds could improve the differentiation rate of neurons. After NSCs and ASCs were cocultured on electrospinning PCL scaffolds, ASCs could express MBP and NSCs could differentiate into neurons, which distributed around those ASCs expressing MBP. Conclusion: Electrospinning PCL fibrous scaffolds showed good biocompatibility, and the fibers had an inducing effect on the distribution of ASCs. NSCs and ASCs cultured on electrospinning PCL scaffolds could form 3D culture system, and NSCs could differentiate into neurons which distributed around the ASCs expressing MBP.
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