Nature: The "regenerating" miracle of pluripotent stem cells

Replacing diseased or damaged cells is a major goal of regenerative medicine

Pluripotent stem cells (PSCs) are capable of self-renewal and self-replication, and have the potential to differentiate into almost any type of cells in the human body, and have great potential in the development of regenerative medicine

However, achieving a stable supply of PSCs is a challenge

For example, iPSC-based therapies could replace neurons that die in Parkinson's disease, retinal tissue damaged by macular degeneration, or could obviate the need for heart transplants

In June 2021, BlueRock Therapeutics, a biotech company headquartered in Massachusetts, USA, launched an open-label Phase I clinical trial of pluripotent stem cell therapy DA01 for Parkinson's disease patients, and was granted Fast Track by the US FDA in July.

However, PSCs still have several issues to be resolved, such as where to obtain the cells

Researchers are trying to solve these problems with tools such as gene editing and make iPSC-based treatments more effective

Cardiovascular diseases

Cardiovascular disease is the leading cause of death in the population of developed countries

Human iPSCs can differentiate into cardiomyocytes, beating muscle cells whose death can lead to heart failure

iPSCs can differentiate into cardiomyocytes, but researchers need to fine-tune them before testing them in patients (Credit: Nature)

But iPSC-based treatments for cardiovascular disease also have some unique challenges

Mummery and her colleagues are developing methods to mature differentiated heart cells

Overall, iPSC-based models of heart disease developed the fastest

Parkinson's Disease

Parkinson's disease is a neurodegenerative disease that affects more than 10 million people worldwide and is characterized by the progressive loss of dopamine-producing midbrain neurons, leading to tremors and other motor and neurological symptoms

The researchers hope that iPSC therapy will replace neurons that die during Parkinson's disease progression

However, the brain is a difficult organ to reach

Neurons derived from stem cells have the potential to replace those lost to Parkinson's disease

Bayer is developing viral vectors to deliver gene segments into the midbrain
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One of the genes encodes GDNF, a growth factor that promotes the survival of dopamine-producing neurons
.
Animal model studies show that delivery of GDNF to the midbrain improves fusion of human stem cell-derived neurons
.
Meanwhile, BlueRock is conducting clinical trials of PSC-derived midbrain dopaminergic neurons
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In early January 2022, BlueRock announced the completion of the first of two arms of its open-label Phase I clinical trial of pluripotent stem cell-derived dopaminergic neurons in patients with advanced Parkinson's disease
.
Patients in the first group underwent bilateral surgery to transplant dopaminergic neurons into their midbrain regions
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No serious adverse events have been observed in any of the enrolled patients
.

macular degeneration

A state-of-the-art regenerative therapy is currently being used to treat age-related macular degeneration (AMD)
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A key issue in AMD is the progressive loss of the retinal pigment epithelium, a layer of cells that protect and regulate photoreceptors
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AMD primarily affects people over the age of 65 and accounts for nearly 9% of global blindness
.

Wet AMD, in particular, is associated with overproduction of vascular endothelial growth factor (VEGF), leading to abnormal growth and leakage of retinal blood vessels
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While the disease can be treated with injections of anti-VEGF drugs, this does not prevent the underlying degeneration
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Relapses are common if treatment is stopped
.

The eyes are easier to access surgically than the brain
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Like the brain, the eye is an immune-privileged organ whose local immune system is less likely to attack foreign cells or tissues
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In addition, the adult mammalian retina retains some regenerative capacity, which raises the prospect of growing new cells from resident progenitors
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However, despite more than a decade of research, developing cell therapies for AMD has remained elusive
.

In 2017, Masayo Takahashi, an ophthalmologist and stem cell researcher at RIKEN, RIKEN, Japan, and his team reported that patient-derived retinal pigment epithelial cells differentiated from iPSCs survived a year after implantation in two patients
.

One of the goals of regenerative medicine is to replace retinal cells lost in macular degeneration (Credit: Nature)

When it comes to using allogeneic materials, Takahashi's team chooses patients carefully
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They looked for patients whose immune systems matched the cell line used for the therapy
.

Pluripotent potential for next-generation therapies

The therapeutic prospects of iPSC therapy go far beyond the above-mentioned diseases, and start-ups and pharmaceutical giants in this field are trying to further optimize the combination of technologies
.

Take Bayer as an example, which integrates iPSC technology, gene editing and virus delivery strategies under the company's cell and gene therapy platform established in 2020
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The platform aims to develop breakthrough innovative therapies to strengthen the company's strategic position in regenerative medicine
.

Meanwhile, Bayer researchers are developing genetic circuits to precisely engineer iPSCs to sense and respond to specific disease markers around them
.

As for the autologous versus allogeneic cell debate, this remains an open question, involving trade-offs between the risk of immune rejection, time, and cost
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But it may not be necessary to choose just one or the other
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Note: The original text has been deleted

References:

New cells for old: The emerging potential of pluripotent stemcells in regenerative medicine (Source: Nature)