Current State of Stem Cell Treatments for Cerebral Palsy: A Guide for Patients, Families, and Service Providers

Please annotation that terms inbold are divers in the glossary, which can be found at the lesser of the folio.

Stem Cells and Cognitive Palsy

Cerebral palsy (CP) is an umbrella term used to describe a disorder that results from perinatal brain injury. CP tin be caused by a multitude of factors, including premature nascency, infection in the uterus, lack of nutritional back up during evolution, lack of oxygen at the time of nascence, and genetic aberrations. While the cause of CP is multifactorial, the injury consistently leads to various neuro-motor deficits, often accompanied by other symptoms, such as visual and cerebral impairments.

When an insult occurs to the encephalon during the sensitive perinatal period, the resident encephalon cells are unable to promote proper growth and development of the brain. Neurons and oligodendrocytes dice and/or fail to mature, and the white matter tracts that connect diverse brain regions become damaged. Importantly, the corticospinal tract (CST), which connects the motor regions of the encephalon to the spinal cord and helps command movement, is often damaged. Without functional CST connections, motor deficits ensue.

Stalk prison cell transplantation is a regenerative therapy that has the potential to supersede the damaged and non-functional cells in the brains of CP patients, too as to provide back up to the remaining neurons and oligodendrocytes. In that location are many kinds of stem cells, each with different and unique characteristics.

Every bit research has advanced, nosotros take discovered that stalk cells can be induced to become more specialized cell types, and when transplanted into the body, they tin can provide support to a damaged environment. In addition, we can modify these stem cells to limited certain factors that can heighten this ability. We tin can also modify the cells to limited scar-degrading factors that can aid to reduce scarring in the brain and promote recovery.

There is a plethora of research in the field of stem prison cell transplantation for CP, and this will be discussed below in the context of both preclinical animate being inquiry and clinical trials.

What are Stalk Cells?

At that place are two characteristics that make stem cells unique from other cells in the torso. Get-go, they have the ability to divide and brand copies of themselves over extended periods of time. Second, they tin differentiate into more specified functional jail cell types. This ways they can transform into specialized cell types of the trunk such as heart, lung, or brain cells. The two characteristics of long-term cell sectionalisation and differentiation capacity have some very important implications for regenerative therapeutic strategies. The ability of stem cells to create copies of themselves over long periods means that their supply is theoretically limitless; nether optimal conditions, a stem cell can be grown in a civilisation dish and terminate up forming colonies of stalk cells. After generating a large pool of stem cells, they can be directed to transform into more than specialized prison cell types, assuming the scientist knows the right factors that will pb to the desired change. Below, we will hash out some of the most of import stem cell types relevant to the treatment of CP, besides as their pros and cons for utilize in inquiry and the clinic.

Embryonic stem cells (ESCs) are plant in the developing embryo. These cells are known as pluripotent, meaning they have the potential to differentiate into all the cell types found in the human torso. ESCs have been studied extensively in social club to empathize the molecular pathways that regulate their "stem cell-ness", along with those pathways that guide differentiation to more specialized cell types (for example, how does one ESC become a neuron and some other a skin cell?). ESCs have unique potential for repairing damaged tissue because of their versatile differentiation chapters. This means that ESCs could be used to care for a vast number of disorders. All the same, scientists are yet working to piece together the right biological codes that can fully differentiate an ESC into the desired cell blazon. A result of non nonetheless understanding the total molecular picture is that ESC-derived cells tin can sometimes revert dorsum into pluripotent cells and form tumours. Another drawback is that the derivation of ESCs requires the employ of cells from the embryo, thus raising moral and ethical dilemmas.

In 2008, Professor Shinya Yamanaka won the Nobel Prize for discovering four biological factors that could be used to plow any somatic (fully differentiated) cell into a pluripotent stem cell. These new, ESC-like cells were termed induced pluripotent stem cells (iPSCs). Post-obit this discovery, there was a peachy excitement in the scientific community. Existence able to create pluripotent stem cells substantially eliminates the need for embryonic tissue in gild to obtain pluripotent stalk cells. This was not the end of the excitement though; Unremarkably, if a patient is to receive a stem cell transplantation, a donor for these cells is required (allogeneic transplantation). iPSCs, nonetheless, can be derived from the patient'south ain somatic cells. First, a biopsy of somatic cells (e.thou. skin cells) would be taken; the cells would then be induced into iPSCs in a culture dish and allowed to divide. Following sectionalisation, the iPSCs could be differentiated into any cell blazon and so placed dorsum into the patient (autologous transplantation) Not needing a donor to acquire the cells significantly reduces the risk of rejection following transplantation into the patient. Despite the enthusiasm surrounding these cells, iPSC-derived cells all the same present a adventure of neoplasm formation, similar to ESCs. Farther research is needed to better empathize the molecular pathways underlying "stem cell-ness" and differentiation processes so that the safety and efficacy of these cells tin can exist optimized for regenerative therapies. Interestingly, in contempo years, new engineering science has allowed for the investigation of directly reprogrammed cells. In this case, somatic cells tin can be straight transformed into the desired cell blazon, essentially by-passing the pluripotent stage that is required when using iPSC technology. One benefit of these directly reprogrammed cells is the reduced risk for tumour germination; however, further enquiry is needed in order to fully understand how we tin can generate these cells in a safe and efficient way.


​While ESCs and iPSCs are excellent sources for versatile cells, they are non convenient for transplantation on their own (due to tumour formation), and and so they are nigh always induced to differentiate into more specialized cell types earlier transplantation.

Neural forerunner cells (NPCs) are stalk cells that are plant in humans within the central nervous organisation (CNS). These stalk cells are more than differentiated than pluripotent stem cells, in that they can simply differentiate into the cells that are institute in the CNS. Accordingly, they are chosen multipotent stem cells. NPCs can be taken from a donor or the patient, grown in a civilization dish so transplanted into the patient. NPCs have a unique benefit over other jail cell types to treat CP; their ability to differentiate into brain cells provides them with the greatest potential to accordingly integrate into the injured brain and replace the damaged and nonfunctional cells. However, the drawback to using NPCs is that there is a limited supply of these cells, and while they tin can be grown in civilisation, the method of retrieval from the brain or spinal cord is very invasive. In addition, these cells are incredibly circuitous and at that place is limited research on their use for treating CP. Conversely, some benefits include: no ethical dilemmas with their derivation, they tin exist taken from the patient so the risk of rejection is minimized upon transplantation, and the fourth dimension required to civilisation the cells is shorter than for pluripotent stem cells, since they are already in the desired format.

Mesenchymal stromal cells (MSCs) are another kind of stem cell that have been used in inquiry surrounding CP. These cells have 2 master origins, either from the bone marrow (BMMSCs) or from the umbilical cord blood (UC-MSCs). Like NPCs, MSCs are multipotent, and they accept the potential to differentiate into various cell types that play structural and immune roles in the body. MSCs take been used in research and the clinic for decades. Their benefits lie in their easy accessibility and their immune-modulation properties. However, MSCs lack the full potential to fully differentiate into functional cells of the CNS, and for this reason, they are unlikely to exist the major focus of time to come multipotent stalk jail cell research for CP.

Sources of Stem Cells for Transplantation

When discussing transplantation strategies, all stem cells, regardless of their type, can either be classified as allogeneic or autologous. Allogeneic cells are those taken from a donor and given to a patient, whereas autologous cells are derived from the patient. Allogeneic stem cells have benefits in that large stalk jail cell banks can be created that can freeze and store stem jail cell donations for extended periods of time. When needed, the cells can be thawed and given to the patient in a short amount of time. A downside to allogeneic cells, nonetheless, is that there is a high risk of immune rejection upon transplantation, since the cells come from a donor. Conversely, autologous stem cells pose minimal gamble for immune rejection, since they come from the patient. Even so, the process for extracting the cells, and culturing them can be lengthy, and if cells are needed within a short time frame, this method is inconvenient.


​Preclinical Stalk Jail cell Research

CP researchers accept been utilizing various cell types, including ESC- and iPSC-derived NPCs, MSCs, equally well as multipotent NPCs found in the brain. Results accept been promising in that stem cell transplantation has resulted in minor functional improvements and positive anatomical changes within the brain.

Equally a part of the Kids Brain Health Network preclinical research team, Dr. Michael Fehlings and his laboratory (Krembil Research Establish, University Health Network and University of Toronto) are currently investigating NPCs and human being iPSC-derived NPCs for the treatment of CP. The squad is developing reproducible fauna models of CP and injecting these stalk cells into the brain. Importantly, the focus of this research is to utilize stem cells as a treatment in a chronic injury context. This means that we are designing stem prison cell therapies that will be efficacious long later the brain injury has occurred.

In preclinical models a few of the hurdles that need to be overcome are: improving cell survival in the brain following transplantation, reducing the chance of neoplasm germination (in the context of pluripotent-derived cells), and understanding how we can strength our transplanted cells to integrate meliorate into the existing neuronal pathways.

Despite these challenges, the noesis gleaned from how stem cells function and incorporate into the damaged CNS is incredibly useful. This information has helped researchers to advance their strategies for jail cell transplantation, likewise as to meliorate understand the roles of endogenous NPCs (stem cells found within the brain) following brain injury.

Stem Jail cell Therapy Clinical Trials

Currently in that location are 12 clinical trials around the earth using stem cells to care for CP. Four of these are recruiting, one is agile only not recruiting, and 7 take been completed. Many of these trials are making use of bone marrow/blood-derived mononuclear cells (a combination of cells originally found in the os marrow that contain hematopoietic stem cells (stalk cells that give rise to red and white blood cells, also termed HSCs) and BM-MSCs). Others are using purified HSCs, or umbilical cord blood containing UC-MSCs and HSCs. Many of these trials have passed the initial phases of clinical trials that only seek to evaluate the right dosage and safety of the intervention. These trials are actually beginning to examination the efficacy of these stem cells as treatments for CP.

To engagement, the findings of only one study have been published. This study had 3 groups of child participants: Those receiving conventional rehabilitation therapy only, those receiving a drug called erythropoietin (shown to accept promise in treating CP) along with conventional rehabilitation therapy, or those receiving umbilical cord claret (containing stem cells) + erythropoietin + conventional rehabilitation therapy. The report found that the group who received stem cells showed greater improvements on cognitive and motor assessments when compared to the other treatment arms.

While the growth in the number of clinical trials since the final edition of this manuscript in 2011 (four vs. the current 12) is exciting and holds promise for the future of stem cell therapies for CP, in that location is still a long way to go. None of the clinical trials to engagement have used NPCs or iPSC-sourced cells, which, as discussed higher up, take unique advantages. NPCs take the greatest potential to integrate into the damaged brain, and being able to use iPSC-derived cells will heavily reduce the need for stem cell donors, thereby minimizing the run a risk of rejection upon transplantation into the patient. iPSCs as well hold the potential to be differentiated into whatever cell type. This versatility will exist quite useful as more research is conducted on unlike cell types for the handling of CP. Even so, learning how to fully command both NPCs and iPSCs and maximize their potential is an ongoing area of research that requires a lot of time and coin. Researchers have been working hard though, and with the assistance of all-encompassing collaborations, funding, and dedication, the world's first iPSC clinical trial (RIKEN trial for age-related macular degeneration), put on concord in early on 2015, has resumed.

Manufacturing and Regulatory Issues

Despite the progress seen with clinical trials in recent years, there are some hurdles that need to be overcome in order for stalk cells to go a widely accessible treatment. 1 of the major issues currently facing the stem cell community is the trouble of "scale up". In the laboratory, stem cells are cultured in Petri dishes. It is feasible to utilize this arroyo to treat one or 2 patients, but as stalk cell therapies come closer to the clinic in that location is an increasing need to develop strategies to manufacture cells on a large scale. Tools chosen bioreactors are a promising arroyo to solve this problem, however, with new large-calibration production strategies, the protocols for cell production will need to be re-evaluated and the efficiencies of prison cell production will change. More inquiry is needed in order to meliorate understand how we can produce our desired stalk cells in mass quantities.

The other problem is that regulatory agencies, such every bit the FDA and Health Canada are having difficulty developing standardized guidelines for the production and employ of stem cells. Not only will individual regulations exist required for each unique jail cell type, but also cells are a completely different biological therapeutic when compared to conventional drugs. Cells are living entities and their effects on the human being body volition not be as well divers. At that place is an urgent need to better constitute these guidelines, as well equally to standardize the manufacturing process in social club to reduce variability among the cells during product. At the bones science level, some of these challenges volition be overcome by improving our understanding of the mechanisms underlying how the cells work. Bones scientists, clinicians, manufacture partners, regulatory agencies, and patient advocates all need to piece of work together to help stem cell therapies move forward.

Stem Cell Tourism

While the North American medical community is working to meliorate constitute stem cell therapies for CP, it is of import to be cautious of unregulated overseas stem cell clinics. The act of going to these unregulated clinics is called "stem cell tourism". While it may seem tempting to do then, and the testimonials on these clinics' websites wait promising, have heed; Stem jail cell transplantation is nevertheless an unproven treatment and while in that location are certainly cases of reported recovery, there are also many incidences of increasing disability. Many of the clinics use the aforementioned types of stem cells to care for a host of dissimilar disorders despite the lack of bear witness to support their employ. The treatments are costly and the risk to patients is enormous. If you are interested in stem cell therapies for yourself or a loved 1, it is strongly advised to go through reputable routes and access registered clinical trials.

Risks and Limitations of Stalk Cell Therapy

Information technology must be cautioned that stem cell therapy is still an experimental technique that is non ready to be adopted as the standard of care for patients with CP. As mentioned previously, the chance of tumour formation is a hurdle that must be overcome. This is an important event to address, because once injected into the body, stem cells cannot be removed. At present it is still non well known as to whether or non the "reprogramming process" of ESCs and iPSCs to more than differentiated prison cell types is a leading cause of tumour formation. Several research projects are currently underway to reduce and if possible eliminate the generation of rogue stem cells that could be tumour-forming. The bug of "calibration-up" and creating well-divers regulatory guidelines for the utilise of stem cells in the clinic must also be addressed.

The promise of stem prison cell therapy is neat and heralds a potential revolution in medicine past providing new therapies for previously untreatable conditions. However, it is unlikely to provide a ane-finish magic bullet to convalesce all clinical symptoms. In the case of CP, stalk cell therapy is probable to result in small incremental improvements in function that in turn volition lead to noticeable improvements in the quality of life for well-nigh patients. Additionally, at present it is non known for how long the beneficial effects of stem cell transplantation volition concluding, and if multiple transplantations of stem cells over several years will be required to better or maintain functional recovery.

As a community, it is important that we manage our expectations of stem prison cell therapies. As mentioned above, this handling is still undergoing development and is non yet widely accepted in the clinic. While stem cell therapies have huge potential for the future handling of CP, the study of these cells is a lengthy process that requires extensive investment of fourth dimension and money. Support of the inquiry that is moving stalk prison cell therapies forward volition assist to fasttrack this therapeutic to the forefront of medicine within the adjacent 20 years.

Table i: The Pros and Cons of Unlike Stem Cell Types

Pros Cons
ESC-Derived Cells

 - Tin can differentiate into whatsoever prison cell blazon the user desires

- Well-studied

- Destruction of any embryo

- Risk of neoplasm formation

- Long procedure to obtain desired cell type
iPSC-Derived Cells

 - Tin differentiate into any cell type the user desires

- Can exist derived from patient'south own cells then there is minimal risk of rejection upon transplantation

- Adventure of tumour germination

- Long process to obtain desired prison cell blazon
Multipotent Stem Cells (e.g. NPCs, MSCs, HSCs)

- Already be in the desired format within the torso

- Low risk of tumour formation

 - Potentially invasive process to retrieve the cells

- Express supply

- If the patient has genetic risk factors, these genes will persist in these cells if taken from the patient. Can be overcome by using a donor, but this increases the risk of rejection

Glossary

Perinatal – Effectually the time of birth

Central nervous system — The brain and spinal cord

Neurons – Cells in the brain that send signals in club to communicate with other regions of the encephalon and the trunk.

Axons – Long processes attached to neurons that relay electrical signals. Coordinating to wires in an electric excursion.

Oligodendrocytes – Produce myelin, a fat that insulates neuronal axons so that neurons can send signals speedily.

White thing tract – A bundle of axons connecting two different regions of the central nervous system.

Regenerative therapy — A therapy that seeks to restore the integrity of damaged tissue. Regenerative therapies using stem cells ofttimes seek to replace dead cells and back up the remaining cells.

Differentiate — The ability to transform into specialized cell types found in the trunk. Once differentiated, the cells cannot become back to their previous state.

Pluripotent – A term used to describe certain stem cells that tin can differentiate into all the different cell types found in the human torso.

Somatic cell – A fully differentiated jail cell found in the human torso (for instance, a skin cell).

Direct reprogrammed prison cell – A somatic cell that has been directly transformed into the desired cell type. This cell has by-passed the pluripotent state that is required when making iPSCderived cells (run into section on induced pluripotent stem cells).

Multipotent — Stalk cells that tin just differentiate into specific cell types. For instance, a neural forerunner prison cell can only differentiate into the cell types constitute in the encephalon and spinal string and not into prison cell types found in the pare.

Allogeneic stem cell transplantation – Stem cells that are taken from a donor and given to a patient. Poses a high risk of immune rejection.

Autologous stem cell transplantation – Stem cells that are taken from a patient and afterward culturing, are transplanted dorsum into the patient. Minimal adventure of immune rejection, but the preparation of the cells takes a long time.

Endogenous – Residing inside a tissue. This is opposed to "exogenous", which means from "outside" the tissue.