Proton MR Spectroscopy of Neural Stem Cells: Does the Proton-NMR Peak at 1.28 ppm Function As a Biomarker for Cell Type or State?

Abstract

Recently, a peak at 1.28 ppm in proton magnetic resonance spectroscopy ( 1 H-MRS) of neural stem cells (NSCs) was introduced as a noninterventional biomarker for neurogenesis in vivo. This would be an urgently needed requisite for translational studies in humans regarding the beneficial role of adult neurogenesis for the structural and functional integrity of the brain. However, many concerns have risen about the validity of the proposed signal as a specific marker for NSCs. The peak has also been related to cell-type-independent phenomena such as apoptosis or necrosis. Thus, we compared the 1.28-ppm peak in various immature stem cell populations, including embryonic stem cells, mouse embryonic fibroblasts, embryonic stem cell-and induced pluripotent stem cell-derived NSCs, ex vivo isolated embryonic NSCs, as well as mature and tumor cell types from different germ layers. To correlate the integral peak intensity with cell death, we induced both apoptosis with camptothecin and necrosis with sodium azide. A peak at 1.28 ppm was found in most cell types, and in most, but not all, NSCH cultures, demonstrating no specificity for NSCs. The intensities of the 1.28-ppm resonance significantly correlated with the rate of apoptosis, but not with the rate of necrosis, cell cycle phase distribution, cell size, or type. Multiple regression analysis displayed a significant predictive value of the peak intensity for apoptosis only. In this context, its specificity for apoptosis as a major selection process during neurogenesis may suggest this resonance as an indirect marker for neurogenesis in vivo.

Metabolic Profiling of Dividing Cells in Live Rodent Brain by Proton Magnetic Resonance Spectroscopy (1HMRS) and LCModel Analysis

“…Newly synthesized DNA of proliferating cells incorporates 18 F-FLT much the same way it incorporates halogenated thymidine analogs 5-bromo, or 5-chloro-2′-deoxyuridine (BrdU and CldU), thus enabling the use of PET for the detection of dividing cells, including neuronal progenitors [5], [7], [8]. Another imaging technique which has been tested for tracking of neurogenesis in the live brain is proton magnetic resonance spectroscopy ( 1 HMRS) [9]–[11]. For example, a previous 1 HMRS study applied singular value decomposition processing algorithms [10] and reported detection of neurogenesis in the hippocampus of the live rodent brain after repetitive electroconvulsive shock (ECS) treatments via increases in a lipid-like spectral signature resonating at 1.28 ppm [10], [12].…”

Profiling metabolite changes in the neuronal differentiation of human striatal neural stem cells using 1H-magnetic resonance spectroscopy

“…Still, mI is an abundant metabolite in the adult brain and thought to act as an osmolyte, while being located in glial cells and to a lesser extent in neurons [17]. This metabolite profile therefore is useful to generally describe the NSC state, but is unlikely to specifically define NSCs per se [18]. …”

Deconstructing stem cell population heterogeneity: Single-cell analysis and modeling approaches

“…For example, stem cells implanted in the circle of Willis of Parkinson patients, were monitored via NMRS in a clinical magnetic resonance imaging (MRI) scanner (Brazzini et al, 2010). Moreover, mobile lipids have been detected via proton magnetic resonance in ESCs and ESC- and iPSC-derived neural stem cells (Loewenbruck et al, 2011). Choline-containing compounds linked to cell proliferation have also been monitored via NMRS in self-renewing and differentiating stem cells.…”