Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

Abstract

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder.

Progenitor cell-based treatment of glial disease

“…Of note, the glial donor cells were isolated on the basis of CD44, the hyaluronan receptor, so as to capture a more astrocyte-biased donor cell population. This neonatal engraftment by CD44-defined glia yielded a transplant-associated fall in neuronal input resistance, and a corresponding drop in interstitial K + in the R6/2 striatum, with an attendant rescue of the otherwise hyperexcitable phenotype of R6/2 striatal neurons (Figures 3D–E) (Benraiss et al, 2016). Together, these studies indicated a critical role for glial pathology in the progression of HD.…”

“…To address this fundamental gap in our knowledge, we used human glial chimeric mice to assess the role of human striatal glia in the pathogenesis of HD, by comparing the behavior and MSN physiology of mice xenografted at birth with mutant HD-expressing human hGPCs to their normal HTT hGPC-engrafted controls (Benraiss et al, 2016). In this study, the motor behavior of immunodeficient mice neonatally xenografted with hGPCs produced from mutant HD human embryonic stem cells (48 CAG) was compared to that of controls engrafted with hGPCs derived from a sibling line of unaffected hESCs (18 CAG).…”

“…Using R6/2 transgenic HD mice as hosts (Mangiarini et al, 1996), Benraiss and colleagues found that the substantial replacement of diseased striatal glia with wild-type human glia indeed resulted in a slowing of disease progression and corresponding increment in survival in transplanted R6/2 mice (Figures 3D–I) (Benraiss et al, 2016). Of note, the glial donor cells were isolated on the basis of CD44, the hyaluronan receptor, so as to capture a more astrocyte-biased donor cell population.…”

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…This study strongly suggests a causal role for glia in HD. 118 mHtt is also expressed in peripheral cells and can alter their normal physiology. mHtt expressed in hepatocytes can suppress the activity of the urea cycle, and can cause high blood ammonia.…”

Human astrocytes are distinct contributors to the complexity of synaptic function

“…Functionally, engrafted human astrocytes present faster calcium wave propagations, confer an increased long term potentiation of neighboring hippocampal neurons and promote an enhancement of learning in several behavior tasks compared to endogenous cells and non-engrafted controls (Han et al, 2013). The transplantation of donor cells into a non-native system has received much attention due to the possible application as therapy, but until the many obstacles that are faced today are overcome, this system may be best applied as a research tool for neurodegeneration and regeneration (Goldman, 2016) as recently demonstrated with Huntington disease chimeras (Benraiss et al, 2016). This type of strategy has also been used as a model for amyotrophic lateral sclerosis and engraftment of human astrocytes expressing mutant SOD1 into a mouse spinal cord resulted in loss of motor neurons and motor function (Chen et al, 2015).…”