Reprogramming Cells to Treat Parkinson's Disease: What the Latest Research Shows

Table of Contents

• Key Points
• What Is Parkinson's Disease?
• Current Treatments and Their Limits
• Early Cell Replacement Therapy: Lessons From Fetal Tissue
• A Newer Graft Source: Human Midbrain Organoids
• How Cellular Reprogramming Works
• Preparing and Purifying the Cells
• Preserving Reprogrammed Cells
• Survival of Transplanted Cells
• Making Cells Mature Into the Right Type
• Direct Cell Reprogramming: Converting Cells Inside the Brain
• Choosing the Best Source Cells
• Summary of Key Research Studies
• Clinical Implications for Patients
• Limitations of the Research
• Recommendations and Outlook
• Frequently Asked Questions
• Source Information

Key Points

• Parkinson's disease involves progressive loss of dopamine neurons; current drugs and deep brain stimulation relieve symptoms only and do not change disease progression.
• In 2018, iPSC-derived dopamine precursor cells were implanted into Parkinson's patients, the first such human trial; the therapy remains experimental.
• Leftover undifferentiated pluripotent cells can form tumors, making purification before transplantation essential; long-term graft survival is low.
• Only A9 dopamine neurons appear to reliably restore motor function; many transplanted neurons never mature into that subtype.
• Direct in situ reprogramming of astrocytes could avoid transplantation, but few nonhuman primate studies exist, so human outcomes are uncertain.

What Is Parkinson's Disease?

Parkinson's disease (PD) is a neurodegenerative disease, meaning it involves the progressive loss of brain cells over time. The defining feature is the degeneration of dopamine neurons (DANs) — brain cells that produce dopamine, a chemical messenger that helps control movement — in a region of the brain called the substantia nigra pars compacta.

These dopamine neurons form part of a circuit known as the nigrostriatal pathway. When these cells die, dopamine levels in a deeper brain region called the striatum fall. This disrupts signaling in the basal ganglia, a group of structures that regulate movement and posture.

The result is a set of hallmark motor symptoms:

• Resting tremor (shaking that occurs when the muscles are relaxed)
• Muscle stiffness (rigidity)
• Bradykinesia (slowed movement)
• Postural instability (difficulty balancing)

As the disease advances, patients may become unable to walk independently. In late stages, many are bedridden for extended periods, which dramatically reduces their quality of life and their ability to care for themselves in daily activities.

Current Treatments and Their Limits

Today, doctors mainly treat PD with two approaches: drug therapy and electrical stimulation. Drug therapy, such as levodopa, is designed to raise dopamine levels in the brain. Deep brain stimulation (DBS) uses implanted electrodes to deliver electrical pulses to specific brain regions.

More recently, researchers have experimented with electrical stimulation intended to boost the brain's own production of neurotrophic factors — naturally occurring proteins that support neuron survival — to slow the loss of dopamine neurons in the substantia nigra.

These treatments have a critical limitation. They can only temporarily relieve symptoms; they do not change the underlying progression of the disease. As PD advances, drug doses must be increased, and the response to treatment gradually diminishes. Because of these limits, researchers have turned to a different idea: replacing the lost dopamine neurons entirely.

Early Cell Replacement Therapy: Lessons From Fetal Tissue

The first attempts at cell replacement used tissue from the human fetal ventral midbrain (fVM) — the embryonic brain region where dopamine neurons form — as a source of donor cells.

These early transplants produced mixed results. Many patients who received the grafts developed dyskinesia (involuntary, uncontrolled movements). Researchers attributed this to two problems: the grafted tissue released dopamine in an unbalanced way, and it had limited ability to reintegrate into the host brain's neural circuits.

Other serious problems included:

• Immune rejection of the transplanted tissue (xenograft rejection, since the tissue came from another source)
• Contamination with other neuron types, such as 5-HTergic neurons (serotonin-producing cells), which further complicated the therapy
• Low purity of the dopamine neurons obtained, meaning a single patient often required tissue from multiple aborted fetuses — a major obstacle to standardizing treatment and applying it on a large scale
• Ethical concerns related to the tissue's origin

Researchers also noted that the stage of disease progression in each patient influenced how well alternative therapies worked, adding another layer of complexity.

A Newer Graft Source: Human Midbrain Organoids

In recent years, scientists have developed an alternative graft source: the human midbrain organoid (hMO). An organoid is a miniature, three-dimensional cluster of cells grown in the lab that mimics aspects of real tissue.

The hMO is derived from induced pluripotent stem cells (iPSCs) — adult cells that have been reprogrammed into a flexible, stem-cell-like state. It is grown under 3D culture conditions and combines the advantages of fetal tissue grafts and two-dimensional dopamine cell cultures.

This has led researchers to consider the hMO a potentially safe and effective donor source for cell therapy in PD.

How Cellular Reprogramming Works

Cell reprogramming refers to transforming a cell from one type (lineage) into another. In the standard approach, scientists convert ordinary body cells — called somatic cells — into induced pluripotent stem cells by forcing them to overexpress four proteins known as the Yamanaka factors: Oct3/4, Sox2, Klf4, and c-Myc (often abbreviated OSKM). Once reprogrammed, these iPSCs can then be guided to differentiate (specialize) into whatever cell type is needed.

The history of this field stretches back more than 60 years. In 1962, J. B. Gurdon first succeeded in reprogramming somatic cells back to a pluripotent-like state. Decades later, Yamanaka identified the key factors that make this possible, marking a true breakthrough for iPSC technology.

Around the same time, R. L. Davis and colleagues found that overexpressing a single protein called MyoD could directly convert fibroblasts (connective-tissue cells) into myoblasts (muscle precursor cells). This was a pivotal finding: it showed that lineage-specific transcription factors — proteins that control which genes are turned on — are sometimes enough on their own to change a cell's fate.

Together, these discoveries opened the door to solving three long-standing problems in dopamine neuron therapy: a limited supply of human dopamine neurons, immune rejection, and ethical concerns.

But creating dopamine neurons from stem cells is far from simple. It faces several obstacles:

1. Low survival rates of transplanted cells in living tissue
2. Unstable or incorrectly formed human embryonic stem cell (hESC)–derived dopamine neurons
3. Low purity before transplantation
4. Risk of tumors from leftover undifferentiated pluripotent cells
5. Ongoing ethical issues surrounding hESC use

Preparing and Purifying the Cells

To turn iPSCs into dopamine neurons, scientists use a carefully staged chemical recipe. First, they apply a technique called dual SMAD inhibition, which uses Noggin (a BMP antagonist, meaning it blocks a specific signaling pathway) and a small molecule called SB431542 (which inhibits TGFβ signaling). This significantly improves the efficiency of neural induction (steering cells toward becoming nerve cells).

Next, the dopamine-producing pattern is initiated in a nutrient solution called N2 medium using a combination of BDNF, ascorbic acid, SHH, and FGF8. Maturation then proceeds in the presence of BDNF, ascorbic acid, GDNF, TGFβ, and cAMP.

Researchers have refined this recipe repeatedly. P. Stathakos and colleagues defined a monolayer protocol for turning human iPSCs into midbrain dopamine (mDA) neurons. They found that FGF8 did not improve the proportion of midbrain cells, but that increasing GDNF and a compound called DAPT (to concentrations of 20 ng/mL and 10 μM, respectively) produced nearly a twofold increase in TH-positive dopamine neurons. TH stands for tyrosine hydroxylase, an enzyme that marks functioning dopamine cells.

Chanda and colleagues made a related discovery: the transcription factor Ascl1 alone was enough to turn embryonic stem cells into dopamine neurons in mice and humans. Adding Nurr1 and Lmx1a did not increase the proportion of TH-positive cells — but the two neurotrophic factors BDNF and GDNF were essential for successful induction.

Testing in nonhuman primates bridges the gap between rodent models and human clinical trials. Studies have shown that transplanting hiPSC-derived dopamine precursor cells can restore striatal dopamine levels and promote motor recovery in both PD rodent and primate models. In 2018, scientists at Kyoto University, Japan, became the first to implant iPSC-derived dopamine precursor cells into the brains of PD patients.

Two major challenges remain: ensuring the safety of transplanted cells, and achieving long-term survival plus reconstruction of neural circuits and restored function. Transplanting incompletely patterned cells risks tumor formation, so purification before transplantation is essential.

Two strategies are used: enriching the desired cells and eliminating unwanted ones (especially pluripotent cells). Scientists initially sorted cells using dopamine neuron surface markers, either by fluorescence-activated cell sorting or immunomagnetic beads.

In 2018, Fathi and colleagues identified new markers — GAP43, GSK3β, and VIM proteins, along with cell surface markers CNTN2, FLOT2, CALB2, and APMAP — that can be used for effective cell sorting and purification. Other approaches include:

• Small molecules such as quercetin and γ-secretase inhibitors (GSIs), which block Notch signaling in dopamine progenitor cells
• A "suicide gene" (cyclinD1-associated thymidine kinase) inserted into iPSC/hESC lines, allowing transduced cells to be selectively destroyed by predrug-activated gene therapy
• Optimization of iPSC differentiation using the DNA crosslinker mitomycin-C (MMC)
• Post-transplant adjuvant radiotherapy
• Designer receptors used as cell surface markers, with monoclonal antibodies to selectively eliminate specific cells

In 2022, Fujita and colleagues built an especially powerful purification system. It uses miRNA-ON and -OFF switches encoding Bn (a deadly RNase that kills cells by degrading RNA) and its inhibitory protein Bs, allowing precise control over which cells survive — achieving a very high degree of cell purification.

Preserving Reprogrammed Cells

Once ideal dopamine neurons are created, they must be stored for delivery to large numbers of patients. That raises two questions: how to freeze cells effectively, and how to ensure they survive thawing while keeping their original characteristics.

Researchers approach this from two directions. First, they choose the right form for freezing — either a single-cell suspension or neurosphere aggregates (clusters of cells). Second, they optimize the freezing protocol, including thaw rate, cell density, freezing volume, and vial type (material and thickness).

Nolbrant and colleagues found that ESC-derived dopamine progenitor cells frozen as a single-cell suspension had a 60% survival rate in the brain after transplantation. Freezing cells as aggregates or neurospheres produced stronger viability after transplant, maintained the 3D structure of donor cells, and was easier to handle — but aggregate freezing is more complex and must be paired with an optimal protocol.

Hiramatsu and colleagues screened six clinical cryoprotectants (substances that protect cells during freezing) and explored six different cooling conditions. They found that Bambanker hRM medium combined with a proton freezer worked best for iPSC-derived dopamine neurospheres. After thawing, the cells showed good viability — including the ability to extend neurites (the branching arms of neurons) — and had the same dopamine-specific markers, dopamine secretion, and electrophysiological activity as freshly prepared cells. One caveat: the maturation of thawed aggregates was delayed inside the body.

Survival of Transplanted Cells

Long-term development, maturation, and survival of the grafted cells must be considered carefully. Relying on short-term survival assessments alone may misjudge the true treatment effect.

Brot and colleagues converted human fibroblasts into hiPSCs using mRNA reprogramming, then transplanted hiPSC-derived dopamine neurons into the substantia nigra pars compacta (SNpc) of PD model mice. They then conducted a comprehensive one-year follow-up.

The findings were revealing. Although transplanting into the substantia nigra repaired the degenerative striatal pathway and induced functional recovery, the number of dopamine neurons lost to apoptosis (programmed cell death) gradually declined over time. The proportion of grafted cells that were proliferating (dividing) was low, and it decreased significantly from 1 to 12 months post-transplantation (1–12 MPT).

At 6 MPT, only 1.3% of cells were proliferating, and all of them belonged to glial cell progenitors (support cells, not neurons). The study also showed for the first time that immature neurons were still present in the graft at 12 MPT.

One key factor affecting transplant efficiency is the developmental stage of the cells used. Studies show that transplanting cells from the late midbrain floor to the mature midbrain dopamine neuroblast stage — or early dopamine neurons — significantly enhances graft development. These stages better maintain innervation-related dopamine targets, increase innervation, and help recover motor defects.

Making Cells Mature Into the Right Type

Not all dopamine neurons are equally useful. Research shows that when host striatal neurons are destroyed, dopamine neuron survival within the graft declines. This matches findings by Brot and colleagues: changes in the dopamine fiber pathway decreased the number of A9 dopamine neuron subsets — the cells critical for restoring motor function — while the A10 subpopulation increased. A significant proportion of transplanted dopamine neurons failed to mature into any specific subtype at all.

This means researchers must track not just long-term survival, but whether transplanted neurons mature into the A9 subpopulation that contributes most to motor recovery.

Using optimal physical, chemical, and developmental cues, researchers developed an efficient and reliable lab technique called the "spotting" method. This method produces midbrain dopamine neurons from hiPSCs that show typical gene expression and electrical characteristics of A9 subsets. When transplanted into the striatum of PD rats with 6-OHDA lesions (a chemical model of Parkinson's), the grafts rescued motor defects.

To increase the proportion of A9 cells, researchers have tried several approaches:

• Lmx1a overexpression: Using lentiviral vectors to drive Lmx1a expression, Sanchez-Danes and colleagues showed that more than 60% of Lmx1a-engineered hESC-derived neurons were A9 subsets. Lmx1a overexpression also increased the A9 proportion in hiPSC-induced dopamine neurons.
• Levodopa combined induction: Transplanting dopamine progenitor cell grafts into the striatum of PD rat models with levodopa increased the number of cells expressing Girk2 (an A9-specific marker), even though it had no effect on the total number of dopamine neurons or fiber growth.

This highlights the need for tailored approaches that account for the biological factors influencing how transplanted neurons develop.

Direct Cell Reprogramming: Converting Cells Inside the Brain

In vitro transplantation faces many limitations: cell purity, tumorigenicity (tumor-forming potential), preservation, resuscitation activity, and post-transplantation survival. This raises a bold question: can cells be reprogrammed directly inside the brain — in situ — into dopamine neurons, or even specifically into A9 neurons?

In 2010, Vierbuchen and colleagues pioneered this concept. By screening 19 candidate genes, they identified a combination of three transcription factors — Ascl1, Brn2 (also known as Pou3f2), and Myt1l — that successfully converted mouse fibroblasts into induced functional neurons (iNs) in the lab.

Direct cell reprogramming — also called direct cell lineage transformation, lineage reprogramming, or trans-differentiation — means converting somatic cells directly into functional neurons without passing through a pluripotent stem cell state. Compared with iPSCs, direct reprogramming is faster and more efficient, and it has unique advantages for tissue repair because it enables in situ transformation within the target tissue. It also avoids ex vivo cell handling, transplantation, and implantation altogether.

The benefits include:

• Short cell induction cycles
• High trans-differentiation efficiency
• Fewer ethical issues
• Reduced risk of tumor formation and immune rejection

Researchers have employed several reprogramming strategies:

1. Viral delivery of specific cell lineage transcription factors
2. Small molecules, protein factors, and drug induction
3. MicroRNA (short RNA molecules that regulate gene activity)
4. Nanomaterials to promote transformation

While significant advances have occurred in rodent models, few studies have attempted in situ reprogramming of dopamine neurons in nonhuman primates — highlighting a clear need for more research in this area.

Choosing the Best Source Cells

Researchers have tried to induce or reprogram dopamine neurons from a wide variety of cell sources, including:

• Adult eye progenitor cells
• Human spermatogonial stem cells
• Human peripheral blood cells
• Amniotic epithelial cells
• Hair follicle stem cells
• Chromaffin progenitor cells
• Mesenchymal cells

Importantly, the origin of different iPSCs significantly affects how well they can differentiate into dopamine neurons at early stages. For future clinical use, source cells need to be readily available. For this reason, fibroblasts and peripheral blood mononuclear cells (PBMCs) are the most frequently studied sources.

For in situ reprogramming therapy in PD, the ideal target cell should be abundant, widely present in the brain (including key regions like the substantia nigra and striatum), and suitable for reprogramming. Astrocytes — star-shaped support cells in the brain — are the most suitable candidates for all these reasons. When the brain has an inflammatory response, many reactive glial cells appear, and these reactive astrocytes at the injury site are prime targets for reprogramming.

Summary of Key Research Studies

The table below summarizes key studies on trans-differentiation of adult cells into dopamine neurons, showing the year, source cells, host, reported efficiency, and method used.

iDANs = induced dopamine neurons; iPAD = induced dopaminergic progenitor cells; Tuj = a marker for neurons; TH = tyrosine hydroxylase (dopamine neuron marker).

Clinical Implications for Patients

This body of research points toward a future in which Parkinson's disease could be treated by replacing the dopamine neurons that patients have lost — potentially halting or reversing the disease rather than just masking its symptoms.

Several developments are particularly relevant to patients:

• Human trials have begun. Since 2018, iPSC-derived dopamine precursor cells have been implanted into PD patients, moving this from laboratory theory into clinical practice.
• Cell purity matters enormously. New purification systems, such as the 2022 miRNA switch technique, allow scientists to remove unwanted cells that could form tumors — a major safety concern.
• Frozen, off-the-shelf products are becoming possible. Improved cryopreservation (freezing) methods mean dopamine neurons could one day be stored and shipped like other medicines, making treatment available to far more patients.
• Targeting the right neuron subtype matters. Only A9 dopamine neurons appear to restore motor function reliably. Techniques like Lmx1a overexpression and levodopa co-treatment can boost the proportion of these critical cells.
• In situ reprogramming could bypass surgery. If scientists can convert a patient's own astrocytes directly into dopamine neurons inside the brain, they could avoid transplantation, immune rejection, and ethical concerns entirely.

The authors emphasize that because PD is complex and patients differ greatly from one another, future treatment will likely still include traditional drugs and upgraded versions of them — cell reprogramming would complement, not replace, existing therapies.

Limitations of the Research

Despite encouraging results, several important limitations remain. Understanding them helps temper expectations and guide future studies.

• Low long-term survival. Even in the best transplants, many dopamine neurons die over time. In one study, only 1.3% of grafted cells were still proliferating at 6 months, and immature neurons persisted a full year after transplant.
• Incomplete maturation. A significant proportion of transplanted neurons never mature into the specific A9 subtype needed for motor recovery.
• Tumor risk. Leftover undifferentiated pluripotent cells can form tumors, making purification essential but technically demanding.
• Few primate studies. Most direct reprogramming work has been done in rodents. Only a handful of studies have tested in situ reprogramming in nonhuman primates, making it hard to predict human outcomes.
• Delayed maturation after freezing. Thawed neurosphere aggregates mature more slowly in the body than fresh cells.
• Variable results by disease stage. A patient's stage of progression affects how well cell replacement works, complicating standardization.

The review also notes that different iPSC origins can affect how well cells differentiate — a variable that must be controlled before large-scale clinical use.

Recommendations and Outlook

Based on the review's findings, several priorities emerge for moving this field forward:

1. Focus on the A9 subtype. Researchers should prioritize methods that reliably produce A9 dopamine neurons, since these are the cells most responsible for restoring movement.
2. Perfect purification before transplant. Removing all pluripotent cells is essential to eliminate tumor risk. Techniques like miRNA switches and suicide genes show the most promise.
3. Optimize the transplant stage. Cells transplanted at the late midbrain floor to early dopamine neuron stage survive and develop best.
4. Improve storage. Continued work on cryoprotectants and freezing protocols will make dopamine neurons more practical for wide clinical use.
5. Expand primate testing. More studies in nonhuman primates are essential before in situ reprogramming can be tested broadly in humans.
6. Consider the patient context. Because outcomes vary by disease stage, treatment plans should be individualized.

For patients and families today, this research is genuinely hopeful but still experimental. Cell reprogramming therapy is not yet a standard treatment option. Anyone considering participation in a clinical trial should discuss risks and benefits carefully with their neurologist. In the meantime, existing treatments — levodopa-based drugs, deep brain stimulation, and physical therapy — remain the standard of care for managing Parkinson's disease.

Frequently Asked Questions

What is Parkinson's disease?

Parkinson's disease is a neurodegenerative condition in which dopamine-producing brain cells in the substantia nigra pars compacta progressively die. This lowers dopamine in the striatum and disrupts movement-regulating circuits, causing resting tremor, stiffness, slowed movement and balance problems. In late stages, many patients become bedridden for extended periods, reducing quality of life and independence.

Why don't current Parkinson's treatments stop the disease?

Drug therapy such as levodopa raises dopamine levels, and deep brain stimulation uses implanted electrodes to deliver electrical pulses. Both can only temporarily relieve symptoms; they do not change the underlying progression of the disease. As Parkinson's advances, drug doses must be increased and the response to treatment gradually diminishes, which is why researchers are exploring replacing lost dopamine neurons.

Have dopamine cell transplants been tested in people?

Yes. In 2018, scientists implanted iPSC-derived dopamine precursor cells into the brains of Parkinson's patients, the first such human trial. Earlier attempts used fetal ventral midbrain tissue, but those grafts produced mixed results, including dyskinesia, immune rejection, contamination with other neuron types, low purity and ethical concerns. Cell reprogramming therapy is still experimental, not a standard treatment option.

What risks are linked to transplanted cells?

Leftover undifferentiated pluripotent cells can form tumors, so purification before transplantation is essential. Immune rejection is another concern, though using a patient's own reprogrammed cells may reduce it. Long-term survival is also low: in one study, only 1.3% of grafted cells were still proliferating at six months, and immature neurons persisted a full year after transplant.

Why does it matter which subtype of dopamine neuron is made?

Not all dopamine neurons are equally useful. Only A9 dopamine neurons appear to reliably restore motor function. In one study, changes in the dopamine fiber pathway decreased A9 subsets while A10 increased, and many transplanted neurons never matured into any specific subtype. Researchers are testing Lmx1a overexpression and levodopa co-treatment to raise the proportion of A9 cells.

Could cells be reprogrammed inside the brain instead of transplanted?

Direct reprogramming converts somatic cells into neurons without passing through a pluripotent stem-cell state. It is faster and more efficient, avoids surgery and transplantation, and may reduce tumor and immune-rejection risk. Astrocytes are considered the most suitable target cells. However, few studies have attempted in situ reprogramming of dopamine neurons in nonhuman primates, so human outcomes remain hard to predict.

What does freezing cells mean for future treatment?

Freezing lets dopamine neurons be stored and shipped like other medicines, potentially making treatment available to far more patients. In one study, ESC-derived dopamine progenitor cells frozen as a single-cell suspension had 60% survival in the brain after transplantation. Aggregate freezing gave stronger viability and kept the 3D structure, but thawed aggregates matured more slowly inside the body.

I have Parkinson's disease and my neurologist mentioned cell reprogramming therapy — when should I seek a second opinion?

Cell reprogramming therapy is not yet a standard treatment option; it remains experimental, and existing treatments such as levodopa-based drugs, deep brain stimulation, and physical therapy remain the standard of care. A second opinion is worth seeking before enrolling in any clinical trial, since outcomes vary by disease stage and treatment plans should be individualized. Discussing risks and benefits carefully with a neurologist helps clarify whether a trial fits your situation. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article title: Somatic cell reprogramming for Parkinson's disease treatment.

Authors: Li X, Fang K, Wang F.

Corresponding author: Fengping Wang, College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, Shandong 261053, China

Publication: Ibrain, 2025; 11:59–73. DOI: 10.1002/ibra.12189

Article type: Review

Funding: National Natural Science Foundation of China, Grant/Award Number: 32400679

Received: May 23, 2024 | Revised: December 4, 2024 | Accepted: December 10, 2024

This patient-friendly article is based on peer-reviewed research published in the open-access journal Ibrain. The original work is distributed under the terms of the Creative Commons Attribution License.