Natural Recovery and Regeneration of the Central Nervous System

Author(s): Chong Tae Kim, MD

Originally published:11/5/2012

Last updated:11/5/2012

1. OVERVIEW AND DESCRIPTION

Since physiatrists may care for patients who have undergone stem cell therapies and are often asked about stem cell therapies by patients who sustain stroke, brain injury, cerebral palsy, degenerative brain diseases, or spinal cord injury, this brief review of neurogenesis and potential uses of stem cells can serve as a quick reference.

Neurogenesis is the process of generating new nerve cells through differentiation from undifferentiated neural progenitor or stem calls. This process is most active in the brain during prenatal development and less active after brain maturation. However, it continues in the hippocampus and subventricular area in the adult brain. Neurogenesis is one of three mechanisms of brain plasticity (two others are synaptic plasticity and functional compensatory processing). Briefly, synaptic plasticity facilitates neural transmission between nerves by enhancing synapses, and functional compensatory processing builds alternate circuits by recruiting inactive areas. The most significant advantage of neurogenesis, compared with other mechanisms of brain plasticity, is its ability to replace injured brain tissue with the same type of tissue at the site. The replaced tissues are expected to resume original function. Three steps are vital for successful neurogenesis: 1) progenitor or stem cell homing into the injured area; 2) cell survival and differentiation; and 3) resumption of proper function.

Undifferentiated neural progenitor cells, or stem cells, differentiate into various types of cells (neurons, glial cells, and other neural lineages), and furthermore, migrate to the site where they are needed. Brain pathology (stroke, seizure, trauma, etc.) provokes endogenous neurogenesis. In animal studies, after acute stroke, active proliferation of neural stem cells develops in the hippocampus and subventricular areas for self-recovery process; however, most cells remain in these areas and do not migrate. A few cells migrate, but do not survive long enough in the migrated areas1 to differentiate. This finding may explain why most stroke patients recover in the early phase and then sustain residual neurological impairment. Improved migration, survival, and differentiation require not only neurogenesis, but also adequate environments (extracellular matrix, angiogenesis).

Multipotent mesenchymal stromal cell (MSC) and neural stem cell (NSC) therapies are currently areas of research. MSCs are commonly obtained from bone marrow, cord blood, placenta, and adipose tissues. They function to provide an optimal environment by way of inflammatory-immunemodulatory-hormonal processes at the lesion sites. Thus, their long term survival at the lesion site is not necessary. On the other hand, NSCs are derived from brain (developing or developed) and able to grow, migrate, differentiate, and function. NCS therapy has emerged as a promising intervention in central nervous system disease/injury. In contrast to animal studies, however, documentation of significant clinical improvements from human NSC therapy for neurogenesis is still lacking.

Without MSC or BSC therapies, voluntary exercise facilitates hippocampal neurogenesis in aging brains and brains with radiation-induced encephalopathy. It is proposed that isolated exercise does not directly affect the neurogeneis, but rather exercise in the context of cognitive challenges.2 Body cooling therapy is also reported to promote neurogensis in animal spinal cord injury; however, there is no scientific research in humans.3

2. RELEVANCE TO CLINICAL PRACTICE

Encouraged by fruitful results from in vitro study of neurogenesis, the use of this modality has been emerging as a potential state-of-the-art treatment for central nervous system diseases. Its application to humans is not yet established, and little research on humans has been reported. Below is a summary of key studies presented to date.

  1. Parkinson’s disease: Nerve fiber outgrowth from transplanted neurons (human embryonic stem cell) was observed and clinical improvement was noted in Parkinson’s patients.4However, the symptoms recurred in some patients on long-term follow-up. In these studies, younger patients benefited more than older ones. Stem cell transplant so far lacks efficacy and sustainability in application to humans, and further, needs to produce long-lasting symptomatic relief without side effects while counteracting Parkinson’s disease progression. Because of this it is not yet suggested as a routine treatment of Parkinson’s disease.
  2. Stroke: Stem cell treatment for stroke is reported to be safe, in spite of the small sample sizes of human studies. The only significant improvement found has been some functional improvement of activities of daily living, but there was no significant improvement of motor function.5 A long-term follow-up case-control study showed improvement of disability by measurement of modified Rankin Scale; however, there was no description about reliability of the measurement.6 Most therapies, at this point, are focused on changing the cellular environment during the penumbral period rather than actual tissue replacement at infracted lesions. Further details of late breaking findings and the results of current studies can be reviewed at http://www.clinicaltrials.gov.
  3. Traumatic brain injury: Human neural stem cells were transplanted into a rat model of traumatic brain injury. Six weeks post-operative follow-up confirmed proliferation, migration (crossed midline), and differentiation of the stem cells.7 Functional recovery was reported in brain-injured rats with human bone marrow stromal cell transplantation.8 As in the other areas, studies for human brain injury are not reported to date.
  4. Spinal cord injury: A major obstacle for the transplantation of neural stem cells (NSCs) into the lesioned spinal cord is their predominant astrocytic differentiation after transplantation. For the last two decades, stem cell treatment for human spinal cord injury was seen as an exciting and promising intervention. It was actually tried in several adult human spinal cord injury patients by a biotechnology company (Geron); however, the project was terminated without any scientific outcomes. There are very few reports about bone marrow stromal cell treatment for human spinal cord injury.9,10 The procedure is reportedly safe, but the positive outcomes were limited. Motor recovery, in particular, was the least impressive, and it was less beneficial in chronic spinal cord injury.
  5. Cerebral palsy: Stem cell therapy in animal models of cerebral palsy reported beneficial effects. Like other areas, no results of clinical in vivo human study are available to date.

3. CUTTING EDGE/UNIQUE CONCEPTS/EMERGING ISSUES

There are several factors to be considered in stem cell therapy.

  1. Delivery routes and methods: systematically (intra-arterial or intravenous) or locally (intraparenchymally, intraventricularly, and intrathecally). NSCs are usually delivered directly into the brain, whereas MSCs are done systematically.
  2. Cell dose: Host environment is the most important factor to decide dose. The principles are to achieve the greatest local benefits with smallest dose without risk of toxicity.
  3. Timing: There is no standard, but the time window is narrow. In animal stroke studies, apoptosis was prevented when administered within 3-24 hours after stroke.
  4. Toxicity: may need immune suppression. Embryonic stem cells and induced pluripotent stem cells have substantial tetratogenic potential. Allogeneic stem cells, especially, may cause graft versus host disease.

4. GAPS IN KNOWLEDGE/EVIDENCE BASE

Safety and efficacy are still not comprehensively reviewed in clinical human studies. Further studies about patient selection and outcome measurement are needed.

The U.S. Food and Drug Administration (FDA) approved open label phase 1 clinical trial for infantile neuronal ceroid lipofuscinosis (Batten disease) for the first time in 2009 (NCT00337636). It was a safe procedure and long-term survival of the transplanted cells was documented, but no functional outcome was mentioned.

Another phase 1 clinical trial in defective myelination of the central nervous system (Pelizaeus-Merzbacher disease) is under investigation (NCT01005004).

REFERENCES

  1. Tonchev AB, Yamashima T, Sawamoto K, Okano H. Enhanced proliferation of progenitor cells in the subventricular zone and limited neuronal production in the striatum and neocortex of adult macaque monkeys after global cerebral ischemia. J Neurosci Res. 2005;81:776-788.
  2. Fabel K, Kempermann G. Physical activity and the regulation of neurogenesis in the adult and aging brain. NeuroMolecular Med. 2008;10(2):59-66.
  3. Kao CH, Chio CC, Lin MT, Yeh CH. Body cooling ameliorating spinal cord injury may be neurogenesis-, anti-inflammation- and angiogenesis-associated in rats. J Trauma-Inj Infect & Crit Care. 2011;70(4):885-93.
  4. Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. NEJM. 2001;344(10):710-719.
  5. Kondziolka D, Steinberg GK, Wechsler L, et al. Neurotransplantation for patients with subcortical motor stroke: a Phase 2 randomized trial. J Neurosurg. 2005;103:38-45.
  6. Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010;28:1099-1106.
  7. Wennersten A, Meier X, Holmin S, Wahlberg L, Mathiesen T. Proliferation, migration, and differentiation of human neural stem/progenitor cells after transplantation into a rat model of traumatic brain injury. J Neurosurg. 2004;100(1):88-96.
  8. Qu C, Mahmood A, Liu XS, et al. The treatment of TBI with human marrow stromal cells impregnated into collagen scaffold: functional outcome and gene expression profile. Brain Res. 2011;1371:129-139.
  9. Yoon SH, Shim YS, Park YH, et al. Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte macrophage-cology stimulating factors: phase I/II clinical trial. Stem Cells. 2007;25:2066-2073.
  10. Pal R, Venkataramana NK, Jan M, et al. Ex vivo-expanded autologous bone marrow-derived mensenchymal stromal cells in human spinal cord injury/paraplegia: a pilot clinical study. Cytotherapy. 2009;11:897-911.

Author Disclosure

Chong Tae Kim, MD
Nothing to Disclose

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