Phenotypic Heterogeneity and Plasticity of Isocortical and Hippocampal Astrocytes in the Human Brain

Abstract

To examine the diversity of astrocytes in the human brain, we immunostained surgical specimens of temporal cortex and hippocampus and autopsy brains for CD44, a plasma membrane protein and extracellular matrix receptor. CD44 antibodies outline the details of astrocyte morphology to a degree not possible with glial fibrillary acidic protein (GFAP) antibodies. CD44ϩ astrocytes could be subdivided into two groups. First, CD44ϩ astrocytes with long processes were consistently found in the subpial area ("interlaminar" astrocytes), the deep isocortical layers, and the hippocampus. Many of these processes ended on blood vessels. Some were also found adjacent to large blood vessels, from which they extended long processes. We observed these CD44ϩ, long-process astrocytes in every brain we examined, from fetal to adult. These astrocytes generally displayed high immunostaining for GFAP, S100␤, and CD44, but low immunostaining for glutamine synthetase, excitatory amino-acid transporter 1 (EAAT1), and EAAT2. Aquaporin 4 (AQP4) appeared distributed all over the cell bodies and processes of the CD44ϩ astrocytes, while, in contrast, AQP4 localized to perivascular end feet in the CD44Ϫ protoplasmic astrocytes. Second, there were CD44ϩ astrocytes without long processes in the cortex. These were not present during gestation or at birth, and in adult brains varied substantially in number, shape, and immunohistochemical phenotype. Many of these displayed a "mixed" morphological and immunocytochemical phenotype between protoplasmic and fibrous astrocytes. We conclude that the diversity of astrocyte populations in the isocortex and archicortex in the human brain reflects both intrinsic and acquired phenotypes, the latter perhaps representing a shift from CD44Ϫ "protoplasmic" to CD44ϩ "fibrous"-like astrocytes.

Morphological plasticity of astroglia: Understanding synaptic microenvironment

“…The human brain appears to exhibit classes of GFAP‐positive cells that are different from cells found in the rodent brain. For instance, in addition to protoplasmic and fibrous astrocytes, interlaminar and varicose projection astrocytes are only found in primates (Colombo and Reisin, 2004; Colombo et al, 1995; Oberheim et al, 2009; Sosunov et al, 2014). Furthermore, human GFAP‐positive protoplasmic astrocytes are larger and more complex than rodent cells (Fig.…”

“…Furthermore, human GFAP‐positive protoplasmic astrocytes are larger and more complex than rodent cells (Fig. 3B), they exhibit enhanced calcium responses, increased calcium wave velocities, and a greater overlap between neighbours (Oberheim et al, 2009; Sosunov et al, 2014). Human and rodent astrocytes also differ with regards to their transcripts (Miller et al, 2010) as do in fact astrocytes from different brain regions (Doyle et al, 2008; Rodriguez et al, 2014; Yeh et al, 2009).…”

The Special Case of Human Astrocytes

“…The latter soon became the experimental paradigm of choice, and human neuroglia were largely neglected for a long time. However, the comprehensive analyses performed during the last decade have revealed extraordinary differences between human and rodent glia, in particular, differences in their astrocytes [49][50][51][52][53].…”

“…Apart from their long varicose processes, these cells otherwise look similar to classical protoplasmic astrocytes, but can be distinguished by their immunopositivity to CD44, also known as the homing cell adhesion molecule [52]. The density of these cells demonstrate remarkable individual variation, and their appearance is somehow related to age; that is, they have never been detected in the neonatal human brain, and it has been speculated that the appearance of these cells may reflect age-dependent adaptive changes and reflect individual life experiences [52]. The evolutionary development of human astrocytes, with processes that span multiple cortical layers, is directly related to the evolution of a highly complex columnar cortical organisation in higher primates.…”

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

“…Intermediate filament proteins are very abundant in the cytoplasmic compartment among all astrocytes types: glial fibrillary acidic protein (GFAP), vimentin, desmin and synemin. Recently, the cell surface marker CD44, the receptor of extracellular matrix hyaluronan, has been described to distinguish, more accurately than GFAP, protoplasmic astrocytes from fibrous-like astrocytes [36] . Resting astrocytes also display specific immunoreactivity for aldehyde dehydrogenase 1 family member L1, AQP4, S100, GLT1, GLAST and glutamine synthetase.…”