Progenitor cell therapy for acquired pediatric nervous system injury: Traumatic brain injury and acquired sensorineural hearing loss

Abstract

While cell therapies hold remarkable promise for replacing injured cells and repairing damaged tissues, cell replacement is not the only means by which these therapies can achieve therapeutic effect. For example, recent publications show that treatment with varieties of adult, multipotent stem cells can improve outcomes in patients with neurological conditions such as traumatic brain injury and hearing loss without directly replacing damaged or lost cells. As the immune system plays a central role in injury response and tissue repair, we here suggest that multipotent stem cell therapies achieve therapeutic effect by altering the immune response to injury, thereby limiting damage due to inflammation and possibly promoting repair. These findings argue for a broader understanding of the mechanisms by which cell therapies can benefit patients.

Keywords: autologous stem cell transplantation; bone marrow; clinical translation; progenitor cells; umbilical cord blood.

FIGURE 1

Mesenchymal stem cell treatment promotes cochlear regeneration in a mouse model of hearing loss. A, Section of organ of Corti (OC) from a control mouse stained with hematoxylin–eosin showing a healthy, intact OC. B, Section of OC from a kanamycin‐treated mouse stained with Lycopersicon esculentum agglutinin (LEA) showing severe degeneration of the OC. C, Section of OC from a kanamycin‐treated mouse 30 days following mesenchymal stem cell injection. The basilar membrane, support cells, hair cells, and overall OC morphology were similar to that of control mice, indicating that mesenchymal stem cell treatment promoted tissue regeneration ⁵²

FIGURE 2

Pediatric traumatic brain injury (TBI) patients treated with mesenchymal progenitor cells (MPCs) exhibited no loss in brain volume at 6 months following injury. Typically, after TBI, there is progressive loss of gray and white matter with an associated increase in CSF volumes. This was not observed in pediatric TBI patients following MPC treatment. Magnetic resonance imaging was used to measure the volume of gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and intracranial volume (ICV) immediately following injury and again at 6 months (scan 2) post‐TBI and MPC treatment. By 6 months following injury, there was no observed decrease in brain volume or increase in CSF volume ¹¹¹

FIGURE 3

Significant improvements in auditory brainstem response (ABR) thresholds were observed in sensorineural hearing loss (SNHL) patients following human umbilical cord blood (hUCB) treatment. Representative ABR thresholds of a responding subject before (baseline) and at 1, 6, and 12 months after hUCB treatment. ABR was measured in the left and right ears in response to air conduction clicks (AC) or tone burst (BR) at a range of frequencies. A greater than 5 dB reduction in ABR threshold is considered a significant improvement. Significant ABR improvements were typically observed at 1 month following treatment, and these improvements were durable through the 12‐month follow‐up period Source: Reprinted with permission, Journal of Audiology and Otology ²⁶

FIGURE 4

Measures of white matter tract integrity correlate with improvements in auditory brainstem response (ABR) threshold in sensorineural hearing loss (SNHL) patients following mesenchymal progenitor cell (MPC) treatment. Mean fractional anisotropy (FA), a measure of white matter integrity, was measured in the left (L) and right Herschel's gyrus before (pre) and after (post) human umbilical cord blood (hUCB) treatment. Patients who showed improved hearing function following treatment (responders), as measured by ABR threshold, exhibited an increase in FA. This increase was not observed in patients who did not exhibit improved ABR thresholds (nonresponders) Source: Reprinted with permission, Journal of Audiology and Otology ²⁶