When I directed PVA’s Spinal Cord Research Foundation a decade ago, function-restoring interventions for spinal cord injury (SCI) were rare and usually off the radar screen in this pre-Internet era. In contrast, today, so many promising surgeries are in the developmental pipeline, it is difficult to keep track of them; at this ever-accelerating rate, the next decade’s progress is anticipated with great excitement. This article’s purpose is to provide brief synopses of some of these surgeries involving the transplantation of various stem or olfactory cells.

Improvements accruing from these surgeries can vary from the negligible to dramatic. Furthermore, results often depend upon the patient’s commitment to aggressive, post-surgical physical rehabilitation designed to maximize restored function, which scientific purists consider a confounding factor. Although impressive success stories receive great visibility, the disappointments do not.

OLFACTORY & STEM CELLS

Because olfactory tissue is exposed to the air we breathe, it contains cells with considerable turnover potential, including renewable neurons, progenitor stem cells, and olfactory ensheathing cells (OECs).

When transplanted into the injured spinal cord, OECs promote axonal regeneration by producing insulating myelin sheaths around both growing and damaged axons, secreting growth factors, and generating structural and matrix macromolecules that lay the tracks for axonal elongation.

Stem cells can differentiate into cells that can potentially treat many neurological disorders. Although a complex subject that cannot be adequately discussed in this article, transplantable stem cells are often categorized as either embryonic, a contentious issue in this country, or adult (non-controversial).

As the name implies, the former are derived from embryonic tissue and possess the greatest potential to differentiate into a wide range of cell types, although it has proven difficult to direct their differentiation pathway.

Adult stem cells are found in numerous tissues, including bone marrow (which produces, for example, hematopoietic stem cells that give rise to blood cells), and nervous tissue (whose stem cells can evolve into neurons and neuronal support cells). Although adult stem cells usually differentiate into the specialized cells associated with the originating tissue, when certain cues are provided, they can differentiate into cells associated with other tissue. For example, under appropriate circumstances, bone-marrow-derived stem cells have the potential to become nerve cells.

Transplantable cells can be obtained from the patient (autologous), different individuals or embryos (allogeneic), or different species (xenogeneic). All three types have been transplanted into the injured spinal cord. Because autologous tissue is from the patient, there is no immunological rejection. Embryonic cells’ undifferentiated nature also minimizes, to some degree, rejection.

In addition to different cells being transplanted, there are differences in how they are re-introduced into the patient. All of the procedural differences help explain why some methods appear so promising and others less so.

SURGICAL PROCEDURES:

Portugal: Dr. Carlos Lima implants whole olfactory tissue obtained from the patient (i.e., no immunological rejection) back into the injury site. Lima believes that more than one cell type is needed to maximize regeneration, including not only OECs but also olfactory neurons in different developmental stages, and precursor stem cells. To date, he has treated over 40 patients, most of whom have accrued benefit. An adult stem-cell advocate, Lima believes “Mother Nature made embryonic stem cells to proliferate and adult stem cells to replace and repair.”

China: In contrast, Dr. Hongyun Huang transplants OECs isolated from fetal olfactory bulbs. The isolated OECs are grown and expanded in culture, and then about a million are injected around the injury site exposed through a limited laminectomy. Huang has transplanted OECs into hundreds of patients, often many years after injury, and there is a long waiting list for his procedures. Because many patients regain some function soon after surgery, improvement is not due to relatively slow neuronal regeneration or remyelination. Huang speculates that OECs wakeup quiescent neurons that still transverse the injury site, perhaps by altering the injury site’s environment through secreting growth factors and producing adhesion and matrix molecules.

Australia: In a phase-1 clinical trial, Dr. Alan MacKay-Sim’s team has implanted autologous OECs back into the patient’s injured cord. The OECs were isolated from the patient’s nasal tissue and amplified in culture to yield up to 20-million cells over six weeks.  These cells were injected into 40 sites surrounding the injury site. The progress of three subjects who received OEC transplants is being compared to three individuals who did not have the transplants. These comparative assessments are blinded, i.e., progress-monitoring assessors do not know which patients had the procedure.

Brazil: Dr. Tarcisio Barros et al. have infused bone-marrow-derived stem cells into the spinal artery closest to the injury site in 32 subjects with clinically complete injuries (2-12 years post injury). The stems cells were isolated from the patient’s own blood after treatment with a drug that stimulates the bone-marrow production of these cells and, in turn, their spillover into the blood. After one-year follow-up, 18 patients have shown improvement in electrophysiological neuronal conduction, which, in some cases, has been translated into functional improvement.

Russia (Moscow): Dr. Andrey Bryukhovetskiy has transplanted embryonic and autologous (i.e., from the patient) adult stem cells into patients with chronic SCI. From extensive experience using both cell types, Bryukhovetskiy has concluded that autologous stem cells are much more effective than the embryonic stem cells in restoring function. With his most recent work, either olfactory or hematopoietic-derived, autologous stem cells are implanted within a gel-polymer matrix for patients who need reconstructive surgeries. In patients who did not need such surgeries, hematopoietic stem cells are transfused intrathecally into the spinal fluid. Although results are preliminary, some of Bryukhovetskiy’s patients (average 5-years post injury) have had dramatic functional improvements in relatively short time periods, many improving two grades using the commonly used ASIA classification scale.

Russia (Novosibirsk): Dr. Samuil Rabinovich’s team has transplanted various combinations of fetal OECs, cells from nervous and hematopoietic tissues, and spinal cord fragments into the injury site of 15 patients. Ranging in age from 18 to 52, patients were one-month to six years post injury and had complete, Frankel grade-A injuries (Frankel classification evolved into today’s ASIA scale). Each patient received one to four cell transplantations at various times, and was followed at least 1.5 years. Improvements were noted in 11 of 15 patients. Six improved to grade-C, incomplete level, and five were able to walk with crutches. In general, patients who had the transplantations sooner after injury accrued the most benefit.

South Korea: Dr. Song Chang-Hoon et al. injected stems cells isolated from umbilical cord blood into a 37-year old woman’s injury site. Injured for 19 years, she regained significant function relatively soon after surgery, including some walker-assisted ambulation. Chang-Hoon believes that injecting the cells directly into the spinal cord is more effective than infusing them into spinal fluid surrounding the cord. Unlike embryonic stem-cells, umbilical stem-cells are not controversial. They also have less rejection potential than most other donor tissue except embryonic tissue; i.e., some, but not strict, matching between donor and recipient is needed.

Czech Republic: Dr. Eva Sykova and colleagues have harvested autologous, bone-marrow stem cells from the iliac bone (i.e., hip) of 17 patients. Within five hours of harvesting, cells were re-introduced into the patient through the vertebral artery (7 cases), intravenously (10 cases), or underneath the cord’s dura membrane (1 case). Eight and nine patients were treated 11-30 days and 2-17½ months after injury, respectively; one patient was treated twice. Four had improved ASIA scores, seven had enhanced neuronal conduction, and the lesions of three were reduced in size as measured by MRI.  In general, more benefits accrued when the treatment was done closer to the time of injury. Sykova is now experimenting with stem cells incorporated within a gel matrix, and treating patients with bone-marrow-derived stem cells that have spilled over into blood after drug stimulation.

Mexico: Starting in the early 1990’s Dr. Fernando Ramirez’ team has transplanted blue-shark, embryonic neuronal cells (i.e., xenogeneic transplantation) into the injured spinal cord of 89 patients with SCI. His approach evolved from live-cell therapies developed by European scientists starting in the 1930s long before stem cells emerged as a hot scientific topic.

CONCLUSION

For a variety of scientific, regulatory, and societal reasons, most SCI surgical breakthroughs are happening elsewhere in the world. Although our conservative approach to developing new treatments ensures safety and efficacy using scientifically pure methodology, it hinders the development of real-world treatments. There is always a tradeoff between the risk of new therapies and the risk of not having any therapies at all. In contrast, for many foreign scientists, there are fewer hurdles to overcome to move beyond animal research to human interventions. To help benefit Americans with SCI, we need to open-mindedly form bridge-building collaborations throughout the world.

Adapted from article appearing in April 2005 Paraplegia News (For subscriptions, call 602-224-0500) or go to www.pn-magazine.com).