In vivo imaging of endogenous neural stem cells in the adult brain

Abstract

The discovery of endogenous neural stem cells (eNSCs) in the adult mammalian brain with their ability to self-renew and differentiate into functional neurons, astrocytes and oligodendrocytes has raised the hope for novel therapies of neurological diseases. Experimentally, those eNSCs can be mobilized in vivo, enhancing regeneration and accelerating functional recovery after, e.g., focal cerebral ischemia, thus constituting a most promising approach in stem cell research. In order to translate those current experimental approaches into a clinical setting in the future, non-invasive imaging methods are required to monitor eNSC activation in a longitudinal and intra-individual manner. As yet, imaging protocols to assess eNSC mobilization non-invasively in the live brain remain scarce, but considerable progress has been made in this field in recent years. This review summarizes and discusses the current imaging modalities suitable to monitor eNSCs in individual experimental animals over time, including optical imaging, magnetic resonance tomography and-spectroscopy, as well as positron emission tomography (PET). Special emphasis is put on the potential of each imaging method for a possible clinical translation, and on the specificity of the signal obtained. PET-imaging with the radiotracer 3'-deoxy-3'-[(18)F]fluoro-L-thymidine in particular constitutes a modality with excellent potential for clinical translation but low specificity; however, concomitant imaging of neuroinflammation is feasible and increases its specificity. The non-invasive imaging strategies presented here allow for the exploitation of novel treatment strategies based upon the regenerative potential of eNSCs, and will help to facilitate a translation into the clinical setting.

Keywords: 3’-deoxy-3’-[18F]fluoro-L-thymidine; Magnetic resonance imaging; Neural stem cells; Positron emission tomography; [11C]PK11195.

Figure 1

Monitoring the migration of endogenous neural stem cell labeled with iron oxide particles in the rat brain in vivo, using magnetic resonance imaging. Migrating cells were imaged 1 d (A), 3 d (B), and 8 d (C) after labeling, migrating from the subventricular zone (left in the sagittal images) to the olfactory bulb (on the right). White circles surround migrating cells. Granot et al[54], with permission. MRI: Magnetic resonance imaging.

Figure 2

[¹⁸F]FLT labels proliferating endogenous neural stem cell in the neurogenic niches of the healthy rodent brain. A, A’: eNSC proliferation in the subventricular zone of adult rats as assessed by [¹⁸F]FLT-PET; B: The signal corresponds to BrdU-positive cells in the region; C: Activation of eNSC by pharmacological stimulation with fibroblast growth factor 2, delta-like 4, and insulin is visualized with [¹⁸F]FLT-PET. eNSC: Endogenous neural stem cell; [¹⁸F]FLT-PET: 3’-deoxy-3’-[¹⁸F]fluoro-L-thymidine-positron emission tomography; i.c.v.: Intracerebroventricular application. Adapted from Rueger et al[75], with permission.

Figure 3

Conclusive differentiation between cell proliferation from endogenous neural stem cell and immune cells. After transient focal ischemia (lesion outlined in white), A: Neuroinflammatory processes are visualized with [¹¹C]PK11195-PET, depicting inflammation in the infarct core as well as in the ischemic border zone; B: [¹⁸F]FLT-PET data acquired in the same imaging session without moving the animals in the scanner demonstrates additional cell proliferation in the subventricular zone (white arrow), originating from endogenous neural stem cells. Adapted from Rueger et al[97], with permission. [¹⁸F]FLT-PET: 3’-deoxy-3’-[¹⁸F]fluoro-L-thymidine-positron emission tomography.