Enriched Environment and Exercise Enhance Stem Cell Therapy for Stroke, Parkinson's Disease, and Huntington's Disease

Abstract

Stem cells, specifically embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), induced pluripotent stem cells (IPSCs), and neural progenitor stem cells (NSCs), are a possible treatment for stroke, Parkinson's disease (PD), and Huntington's disease (HD). Current preclinical data suggest stem cell transplantation is a potential treatment for these chronic conditions that lack effective long-term treatment options. Finding treatments with a wider therapeutic window and harnessing a disease-modifying approach will likely improve clinical outcomes. The overarching concept of stem cell therapy entails the use of immature cells, while key in recapitulating brain development and presents the challenge of young grafted cells forming neural circuitry with the mature host brain cells. To this end, exploring strategies designed to nurture graft-host integration will likely enhance the reconstruction of the elusive neural circuitry. Enriched environment (EE) and exercise facilitate stem cell graft-host reconstruction of neural circuitry. It may involve at least a two-pronged mechanism whereby EE and exercise create a conducive microenvironment in the host brain, allowing the newly transplanted cells to survive, proliferate, and differentiate into neural cells; vice versa, EE and exercise may also train the transplanted immature cells to learn the neurochemical, physiological, and anatomical signals in the brain towards better functional graft-host connectivity.

Keywords: Parkinson’s disease; combination therapy; enriched enviroment; exercise; huntingtons’s disease; rehabiliatation; stem cell; stroke.

FIGURE 1

The disruption in the functional circuit in Parkinson’s disease. In PD, loss of the dopaminergic neurons of the substantia nigra pars compacta (SNc) leads to increased output by the indirect pathway and less motor output. The loss of dopaminergic neurons also impacts the direct pathway, increasing the circuit’s inhibition on the thalamus (VA/VL). Green arrows signify glutamatergic excitatory neurons and red arrows signify GABA expressing inhibitory neurons. enk, enkephalin; SP, Substance P; GPe, globus pallidus, external segment; GPi, globus pallidus, internal segment; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VA/VL, ventral anterior/ventral lateral nucleus of the thalamus; D1r, D1 dopaminergic Gs coupled receptor; D2r dopaminergic Gi coupled receptor. Adapted from (McGregor and Nelson, 2019).

FIGURE 2

The disruption in the functional circuit in Huntington’s disease. Cerebral cortex atrophy and loss of the indirect pathway leads to more motor output and results in the choreiform movements seen in HD. Green arrows signify glutamatergic excitatory neurons and red arrows signify GABA expressing inhibitory neurons. enk, enkephalin; SP, Substance P; GPe, globus pallidus, external segment; GPi, globus pallidus, internal segment; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VA/VL, ventral anterior/ventral lateral nucleus of the thalamus; D1r, D1 dopaminergic Gs coupled receptor; D2r dopaminergic Gi coupled receptor. Adapted from (Essa et al., 2019).

FIGURE 3

Training the stem cell graft to integrate with the host brain. Stem cell transplantation offers many therapeutic benefits such as immune system modulation, dying cell rescue, neurogenesis, and angiogenesis. When combined with the benefits of EE and exercise, these outcomes synergize and lead to better outcomes.

FIGURE 4

A diagram of the classical and simplified functional circuit of the basal ganglia. Dopaminergic neurons from the substantia nigra pars compacta (SNc) project to the medium spiny neurons (MSNs) of the striatum and modulate the direct and indirect pathway activity to modulate inhibition by the thalamus (VA/VL). Green arrows signify glutamatergic excitatory neurons and red arrows signify GABA expressing inhibitory neurons. enk, enkephalin; SP, Substance P; GPe, globus pallidus, external segment; GPi, globus pallidus, internal segment; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; VA/VL, ventral anterior/ventral lateral nucleus of the thalamus; D1r, D1 dopaminergic Gs coupled receptor; D2r dopaminergic Gi coupled receptor. Adapted from (McGregor and Nelson, 2019).