Stem Cells as Potential Therapy for Chronic Pain

Marie Csete MD, PhD

An estimated 30.7% of Americans report chronic pain (chronic, recurrent, or long-lasting pain lasting at least 6 months) [1], making it an incredibly common and poorly treated disease state. Pain can be generally divided into two types: nociceptive and neuropathic. Nociceptive pain is the result of an injury (or surgery) or a lesion putting pressure on a nerve. Pain is usually proportional to the degree of injury, often responsive to opioids, and is usually time-limited—when the injury resolves so does the pain. Neuropathic pain, however, can start with an injury, but has many other causes, the pain is persistent beyond the injury resolution, is often not responsive to opioids, and may be very difficult to treat. Common neuropathic pain syndromes include diabetic neuropathy and post-herpetic neuralgia. Most pre-clinical studies using stem cells to ‘treat’ chronic pain have focused on neuropathic pain models.

Pain ratings (usually visual analog scales) are commonly collected from subjects in a variety of stem cell clinical trials for example, trials targeting critical limb ischemia (inadequate blood supply). In most of these cases, pain is thought of as a symptom of the underlying disease process, and so should resolve in parallel with improvement in the underlying disease (new blood vessels). It is striking when reading results of clinical trials that pain relief from a stem cell intervention may be out of proportion (better than) other end-points of disease resolution (such as regeneration of new blood vessels). This observation suggests that cell therapies could be affecting pain pathways per se, independent of secondary effects on pain expected from treating an ischemic disease process.

It is not surprising that pain has been a target of stem cell therapies. Using a standard model of neuropathic pain, chronic constriction injury of the rat sciatic nerve, pain behaviors were dramatically reduced in rats that received intravenous syngeneic bone marrow mononuclear cells just after the surgical injury was established [2]. In the midst of many related reports of various cell therapy approaches to pain showing positive results, one report did raise caution about the use of bone marrow mononuclear cells. In the context of a preclinical diabetes model, marrow-derived cells can fuse to dorsal root ganglia and the sciatic nerve, inducing production of proinsulin (prohormone precursor of insulin) and tumor necrosis factor (cytokine involved in inflammation) after fusion, contributing to neuropathy [3]. (Bone marrow mononuclear cells are known to be particularly fusogenic—including fusing with hepatocytes [4].)

Not surprisingly, given the anti-inflammatory properties of mesenchymal stem cell (MSC) populations, several groups have tried to use MSC for ameliorating pain. Some of these studies have advanced to the clinic. A pilot study of patients with pain related to (knee) osteoarthritis were treated with autologous marrow-derived MSC given into the affected joint. Pain relief was documented in parallel to some improvement in cartilage quality [5]. Clinicaltrials.gov lists several ongoing trials of MSC for diabetic foot ulcer (with pain as an endpoint).

Other cell therapies show promise for treating pain, taking advantage of mechanisms other than anti-inflammatory effects. Neuropathic pain is associated with loss of inhibition via GABAergic interneurons (cells that output the chemical messenger gamma-aminobutyric acid) at the level of the spinal cord. The Basbaum lab at University of California, San Francisco took a cell therapy approach directed at replacing the lost inhibitory cells. They transplanted mouse embryonic brain neural precursors (destined to become GABAergic neurons) into the spinal cord of mice with pain caused by sciatic nerve injury. The transplanted cells developed into inhibitory neurons and integrated into the peripheral nervous system, resulting in improvement in pain assessed by mechanical hypersensitivity assays [6]. With an eye on translation, the next step for this lab is transplantation of similar human cells into an immunosuppressed mouse model of pain. Other groups have reported similar results using pre-differentiated neural progenitors (pushed toward GABAergic fate before transplantation) in the rat sciatic nerve chronic constriction injury model [7]. These studies raise the interesting question of how dosing can be controlled in such experiments, since an ‘overdose’ of GABAergic tone could be pathologic.

Others have suggested that chromaffin cells (neuroendocrine cells found mostly in the medulla of the adrenal glands) may be useful for pain relief, based on studies performed well before the current stem cell revolution [8]. Chromaffin-like cells generated from reprogrammed human MSC produce preproenkephalin (a precursor for naturally occurring opioid peptides) and show some analgesic effects in preclinical studies [9].

Chronic pain is a debilitating side effect of spinal cord injury [10]. Roger Johns’ group at Johns Hopkins University studied cell therapy in the context of a contusion spinal cord injury. The group used (murine) embryonic stem cell-derived oligodendrocyte precursors transplanted via laminectomy. Laminectomy is a surgical procedure that removes a portion of the bone called the lamina. They found that the pre-oligodendrocytes differentiated into more mature oligodendrocytes (glial cells concerned with production of myelin) after transplantation, and that mechanical allodynia (hypersensitivity) was reduced as a function of transplantation. This study raises the issue of targeting remyelination after spinal cord injury as a way to address chronic pain [11]. Of note, a similar approach was taken by Geron for treating acute thoracic spinal cord injury in a short-lived phase I clinical trial using human embryonic stem cell-derived preoligodendrocytes [12]. No safety issues have been reported for the few patients treated in that trial.

Martin Marsala’s group at University of California, San Diego used human fetal spinal cord-derived (nestin; a filament protein expressed in nerves,-positive) neural stem cell transplantation in an acute rat spinal cord injury model, with cells delivered intraspinally 3 days after injury. In this study hypoesthesia (decreased sensory responses) followed the injury, and both sensory (mechanical and heat) and motor function improved after transplantation [13]. The authors also described a cavity-filling effect of the transplanted cells that they think may be important in preventing syringomyelia (pathologic cavity formation), in addition to some donor cells contributing to GABA-inhibitory synapses.

Neural stem cells are undergoing investigation in clinical trials for chronic spinal cord injury. Sponsored by Stem Cells Inc., and conducted in Switzerland, a trial of fetal-derived neural stem cells injected into the spinal cord of thoracic-level spinal cord injured patients targets cell therapy 3-12 months after injury. Study subjects are transiently immunosuppressed. The trial is meant ultimately to include patients with various severity lesions, classified by the American Spinal Injury Association (ASIA) as Asia A, B, and C. To date, no information is available on the company website about changes in pain patterns in the first patients studied, though no safety issues have been reported [14].

A major caution for stem cell therapies focused on both pain and regeneration is the need for pain mediators in regenerative processes. Certainly myeloid cells play a pro-regenerative role after skeletal muscle [15] and other injuries, such that turning down their function could slow or impair regeneration. Cyclooxygenase-2 (cox-2), an enzyme supplied by inflammatory cells is important for bone [16] and muscle [17] regeneration.

Pain is an extremely complex process, not adequately captured by a single question in quality of life surveys that accompany many clinical trials. For disease processes in which pain is an important end-point of cell therapy clinical studies, involvement of pain experts is an important opportunity for understanding how stem cells work and in turn, for understanding the molecular mediators of pain in various diseases.

References

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  2. Klass M, Gavrikov V, Drury D, Stewart B, Hunter S, Denson DD, Hord A, Csete M: Intravenous mononuclear marrow cells reverse neuropathic pain from experimental mononeuropathy. Anesth Analg 2007; 104:944-8.
  3. Terashima T, Kojima H, Fujimiya M, Matsumura K, Oi J, Hara M, Kashiwagi A, Kimura H, Yasuda H, Chan L: The fusion of bone-marrow-derived proinsulin-expressing cells with nerve cells underlies diabetic neuropathy. Proc Natl Acad Sci U S A 2005; 102:12525-30.
  4. Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M: Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000; 6:1229-34.
  5. Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentis J, Sanchez A, Garcia-Sancho J: Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 2013; 95:1535-41.
  6. Braz JM, Sharif-Naeini R, Vogt D, Kriegstein A, Alvarez-Buylla A, Rubenstien JL, Basbaum AI: Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain. Neuron 2012; 74:663-75.
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  9. Qu T, Shi G, Ma K, Yang HN, Duan WM, Pappas GD: Targeted cell reprogramming produces analgesic chromaffin-like cells from human mesenchymal stem cells. Cell Transplant 2013; 22:2257-66.
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  13. van Gorp S, Leerink M, Kakinnohana O, Platoshyn O, Santucci C, Joosten E, Hruska-Plochani M, Goldbergi D, Marsala S, Johe K, Marsala M: Amelioration of motor/sensory dysfunction and spasticity in a rat model of acute lumbar spinal cord injury by human neural stem cell transplantation. Stem Cell Res Ther 2013; 4(3):57 epub ahead of print.
  14. Piltti KM, Salazar DL, Uchida N, Cummings BJ, Anderson AJ: Safety of human neural stem cell transplantation in chronic spinal cord injury. Stem Cells Transl Med 2013; 2:961-74.
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  16. Xie C, Ming X, Wang Q, Schwarz EM, Guldberg RE, O’Keefe RJ, Zhang X: Cox-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. Bone 2008; 43:1075-83.
  17. Bondesen BA, Mills ST, Kegley KM, Pavlath GK: The cox-2 pathway is essential during early stages of skeletal muscle regeneration. Am J Physiol Cell Physiol 2004; 287:C475-83.

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