Stem cell therapies represent a promising regenerative medicine approach for [neurodegenerative diseases](/diseases/neurodegenerative-disease), offering the potential to replace lost [neurons](/cell-types/neurons), provide neuroprotective support via [BDNF](/proteins/bdnf-protein) and [GDNF](/proteins/gdnf-protein), and modulate [immune responses](/mechanisms/neuroinflammation). Multiple stem cell types are being investigated for conditions including [Parkinson's disease](/diseases/parkinsons-disease), [Alzheimer's disease](/diseases/alzheimers-disease), [Huntington's disease](/diseases/huntingtons), and [amyotrophic lateral sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis)[@cell2023][@stem2022].
Relationship to Neurodegenerative Diseases
Stem cell therapy targets multiple pathological features across [tauopathies](/mechanisms/tauopathies) and [synucleinopathies](/mechanisms/synucleinopathies). In [Alzheimer's disease](/diseases/alzheimers-disease), stem cells can replace [cholinergic neurons](/cell-types/cholinergic-neurons) lost to [amyloid-beta](/proteins/amyloid-beta) plaque-induced toxicity and [tau](/proteins/tau) neurofibrillary tangle formation in the [hippocampus](/brain-regions/hippocampus). For [Parkinson's disease](/diseases/parkinsons-disease), [dopaminergic neurons](/cell-types/dopaminergic-neurons) in the [substantia nigra](/brain-regions/substantia-nigra) are the primary target for replacement, addressing the loss of [dopamine](/proteins/dopamine)-producing cells that drives motor symptoms. [Huntington's disease](/diseases/huntingtons) involves degeneration of [medium spiny neurons](/cell-types/medium-spiny-neurons) in the [striatum](/brain-regions/striatum), which can be targeted with [iPSC](/therapeutics/ipsc-therapy)-derived cells. In [ALS](/diseases/amyotrophic-lateral-sclerosis), [motor neuron](/cell-types/motor-neurons) replacement addresses the progressive weakness caused by [TDP-43](/proteins/tardbp-protein) pathology and excitotoxicity. Stem cells also modulate [microglial](/cell-types/microglia) activation to reduce [neuroinflammation](/mechanisms/neuroinflammation) across all these diseases.
Types of Stem Cells
1. Embryonic Stem Cells (ESCs)
Source: Inner cell mass of blastocysts
Pluripotency: Can differentiate into all three germ layers including [dopaminergic neurons](/cell-types/dopaminergic-neurons) for [Parkinson's disease](/diseases/parkinsons-disease)
Advantages: Unlimited expansion, full differentiation potential for [hippocampal](/brain-regions/hippocampus) neuron replacement
Source: Reprogrammed adult somatic cells via [OCT4](/proteins/oct4-protein), [SOX2](/proteins/sox2-protein), [KLF4](/proteins/klf4-protein) expression
Pluripotency: Equivalent to ESCs for generating [motor neurons](/cell-types/motor-neurons) in [ALS](/diseases/amyotrophic-lateral-sclerosis)
Advantages: Patient-specific via [CRISPR](/technologies/crispr) gene editing, no ethical concerns, immune-matched for [substantia nigra](/brain-regions/substantia-nigra) transplantation
Multipotency: Can differentiate into bone, cartilage, fat for [osteoporosis](/diseases/osteoporosis)-related neurodegeneration
Advantages: Immunomodulatory properties via [TGF-beta](/proteins/tgf-beta-protein) secretion, easily obtained for [ALS](/diseases/amyotrophic-lateral-sclerosis) therapy
Applications: Primarily for immunomodulation reducing [microglial](/cell-types/microglia) activation in [Alzheimer's disease](/diseases/alzheimers-disease)
4. Neural Stem Cells (NSCs)
Source: [Fetal brain tissue](/brain-regions/fetal-brain) or [ESC/iPSC](/therapeutics/ipsc-therapy) differentiation in the [subventricular zone](/brain-regions/subventricular-zone)
Advantages: Natural CNS tropism for [hippocampal](/brain-regions/hippocampus) integration, replacement potential in [substantia nigra](/brain-regions/substantia-nigra)
Challenges: Limited expansion, survival in host [brain](/brain-regions/overview) affected by [alpha-synuclein](/proteins/alpha-synuclein) pathology
5. Direct Reprogramming
Method: Converting [fibroblasts](/cell-types/fibroblasts) directly to [dopaminergic neurons](/cell-types/dopaminergic-neurons) via [ASCL1](/genes/ascl1), [BRN2](/genes/brn2), [MYT1L](/genes/myt1l)
Advantages: No pluripotent stage reducing tumorigenicity, patient-specific for [GBA](/genes/gba)-associated [Parkinson's disease](/diseases/parkinsons-disease)
Status: Preclinical development targeting [striatal](/brain-regions/striatum) neurons
Mechanisms of Action
Cell Replacement
Dopaminergic neurons: For [Parkinson's disease](/diseases/parkinsons-disease) targeting [substantia nigra](/brain-regions/substantia-nigra) [pars compacta](/brain-regions/substantia-nigra-pars-compacta)
Cholinergic neurons: For [Alzheimer's disease](/diseases/alzheimers-disease) targeting [basal forebrain](/brain-regions/basal-forebrain) [cholinergic](/cell-types/cholinergic-neurons) degeneration
Medium spiny neurons: For [Huntington's disease](/diseases/huntingtons) targeting [striatal](/brain-regions/striatum) [GABAergic](/cell-types/gabaergic-neurons) loss
Motor neurons: For [ALS](/diseases/amyotrophic-lateral-sclerosis) targeting [spinal cord](/brain-regions/spinal-cord) [corticospinal](/brain-regions/corticospinal-tract) degeneration
Neuroprotection
Growth factor secretion: [BDNF](/proteins/bdnf-protein), [GDNF](/proteins/gdnf-protein), [NGF](/proteins/nerve-growth-factor) for [dopaminergic neuron](/cell-types/dopaminergic-neurons) survival
Anti-inflammatory effects: Reduced [cytokine](/proteins/cytokines) production via [TGF-beta](/proteins/tgf-beta-protein) modulation in [hippocampus](/brain-regions/hippocampus)
Antioxidant properties: Protection from [oxidative stress](/mechanisms/oxidative-stress) via [glutathione](/proteins/glutathione) enhancement
Synaptic support: Maintaining [neuronal connectivity](/mechanisms/synaptic-plasticity) in [cortex](/brain-regions/cerebral-cortex)
Immunomodulation
T cell modulation: Reducing [autoimmune](/mechanisms/autoimmune-encephalitis) responses affecting [substantia nigra](/brain-regions/substantia-nigra)
Microglial regulation: Shifting to [M2 phenotype](/cell-types/m2-microglia) via [IL-10](/proteins/il-10-protein) secretion to reduce [neuroinflammation](/mechanisms/neuroinflammation)
Anti-apoptotic effects: Preventing [neuron death](/mechanisms/neuronal-death) via [Bcl-2](/proteins/bcl-2-protein) pathway activation
Advantages
Potential for cure: Can replace lost neurons
Disease modeling: Patient iPSCs enable disease study
Survival and integration: Cells often fail to survive and integrate in the [host brain](/brain-regions/overview), particularly in the [toxic](/proteins/alpha-synuclein) environment of [Parkinson's disease](/diseases/parkinsons-disease) [substantia nigra](/brain-regions/substantia-nigra)
Tumorigenicity: Risk of uncontrolled growth in [hippocampus](/brain-regions/hippocampus), especially with [pluripotent cells](/therapeutics/ipsc-therapy) retaining [p53](/proteins/tp53-protein) dysfunction
Immune rejection: Allogeneic cells may be rejected due to [MHC](/proteins/mhc-complex) mismatch in [ALS](/diseases/amyotrophic-lateral-sclerosis) patients
Delivery: Invasive procedures required for CNS delivery to [basal ganglia](/brain-regions/basal-ganglia), requiring precise [stereotactic](/technologies/stereotactic-surgery) targeting
Standardization: Difficult to manufacture consistent [dopaminergic neuron](/cell-types/dopaminergic-neurons) products for [Parkinson's disease](/diseases/parkinsons-disease)
Cost: Extremely expensive to produce patient-specific [iPSC](/therapeutics/ipsc-therapy)-derived cells ([$500K+ per dose](/companies/cost))
Ethical concerns: ESCs face ethical and regulatory hurdles affecting [clinical trials](/clinical-trials/) in [Alzheimer's disease](/diseases/alzheimers-disease)
Long-term effects: Unknown durability of benefits in [tau](/proteins/tau) [neurofibrillary tangle](/mechanisms/tauopathies)-bearing [hippocampus](/brain-regions/hippocampus)
Pathology exposure: Transplanted cells may be affected by [neuroinflammation](/mechanisms/neuroinflammation) and [mitochondrial dysfunction](/mechanisms/mitochondrial-dysfunction) in host tissue
Current Development Stage
Clinical Trials by Disease
Parkinson's Disease
[BlueRock Therapeutics](/companies/bluerock-therapeutics) ([Bayer](/companies/bayer)): Phase I trial with ESC-derived [dopamine neurons](/proteins/dopamine) targeting [substantia nigra](/brain-regions/substantia-nigra)
[International Stem Cell Corporation](/companies/international-stem-cell-corporation): Phase II with parthenogenetic stem cells for [striatal](/brain-regions/striatum) integration
[Multiple hospitals](/institutions/research-hospitals): Various Phase I/II trials worldwide for [dopaminergic neuron](/cell-types/dopaminergic-neurons) transplantation
Status: Early clinical stages; safety signals observed in [basal ganglia](/brain-regions/basal-ganglia)
Alzheimer's Disease
[Longeveron](/companies/longeveron): MSC therapy Phase I/II completed targeting [hippocampal](/brain-regions/hippocampus) [cholinergic](/cell-types/cholinergic-neurons) function
[Multiple](/companies/): Small trials ongoing for [neuroinflammation](/mechanisms/neuroinflammation) modulation via [microglial](/cell-types/microglia) regulation
Challenge: More complex pathology than PD, with [amyloid-beta](/proteins/amyloid-beta) plaques and [tau](/proteins/tau) tangles affecting cell survival
Huntington's Disease
[Neuralstem](/companies/neuralstem): Phase I trial with NSC transplantation targeting [striatal](/brain-regions/striatum) [medium spiny neurons](/cell-types/medium-spiny-neurons)
[Various](/companies/): Multiple early-stage trials for [GABAergic](/cell-types/gabaergic-neurons) neuron replacement
Focus: Replacing [medium spiny neurons](/cell-types/medium-spiny-neurons) in [caudate nucleus](/brain-regions/caudate-nucleus) and [putamen](/brain-regions/putamen)
ALS
[Brainstorm Cell Therapeutics](/companies/brainstorm-cell-therapeutics): Phase III with MSC-NTF cells for [neurotrophic factor](/proteins/gdnf-protein) secretion
[Various](/companies/): Multiple Phase I/II trials via [intrathecal](/techniques/intrathecal-delivery) delivery
Approach: Neuroprotective via [GDNF](/proteins/gdnf-protein) delivery rather than [motor neuron](/cell-types/motor-neurons) replacement
[BlueRock Therapeutics](/companies/bluerock-therapeutics) ([Bayer](/companies/bayer)): ESC-derived [dopamine neurons](/proteins/dopamine) for [Parkinson's disease](/diseases/parkinsons-disease)
[Brainstorm Cell Therapeutics](/companies/brainstorm-cell-therapeutics): MSC-NTF cells for [ALS](/diseases/amyotrophic-lateral-sclerosis) via [neurotrophic](/proteins/gdnf-protein) support
[Fate Therapeutics](/companies/fate-therapeutics): iPSC-derived NK and T cells for [neuroinflammation](/mechanisms/neuroinflammation) modulation
[Celularity](/companies/celularity): Placental-derived stem cells for [Alzheimer's disease](/diseases/alzheimers-disease) immunotherapy
Pharmaceutical Partners
[Bayer](/companies/bayer): [BlueRock acquisition](/companies/bluerock-therapeutics) for cell therapy targeting [substantia nigra](/brain-regions/substantia-nigra)
[Sumitomo](/companies/sumitomo): [Parkinson's cell therapy](/diseases/parkinsons-disease) programs for [dopaminergic neuron](/cell-types/dopaminergic-neurons) replacement
[Astellas](/companies/astellas): [iPSC](/therapeutics/ipsc-therapy) programs for [CNS disease](/diseases/cns-disease) including [tauopathies](/mechanisms/tauopathies)
Academic Programs
[Harvard/MIT](/institutions/harvard): Multiple [iPSC](/therapeutics/ipsc-therapy) programs for [Alzheimer's disease](/diseases/alzheimers-disease) and [ALS](/diseases/amyotrophic-lateral-sclerosis)
[Stanford](/institutions/stanford): NSC transplantation research for [Parkinson's disease](/diseases/parkinsons-disease) in [substantia nigra](/brain-regions/substantia-nigra)
[University of Wisconsin](/institutions/university-wisconsin): ESC differentiation protocols for [dopaminergic neuron](/cell-types/dopaminergic-neurons) generation
[Unknown, Clinical applications of stem cells in neurology (Brain, 2023) (2023)](https://doi.org/10.1093/brain/awad157)
Pathway Diagram
The following diagram shows the key molecular relationships involving Stem Cell Therapies for Neurodegenerative Diseases discovered through SciDEX knowledge graph analysis: