Cellular Transplants in China: Observational Study from the Largest Human Experiment in Chronic Spinal Cord Injury

Dobkin, Bruce H.; Curt, Armin; Guest, James D.

doi:10.1177/1545968305284675

Cited by 195 publications

(119 citation statements)

References 22 publications

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“…Furthermore, using BLI, we demonstrated the presence of an appropriate range in the number of transplanting cells for SCI. In clinical trials, the transplantation protocols are completely different and, in particular, the number of transplanted cells varies considerably, which is also true in animal studies 5,7,8 . This hampers the establishment of an optimal treatment for SCI.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the transplantation of stem cells such as neural stem/progenitor cells (NSPCs) is an exciting therapeutic option for replacing damaged neural cells and inducing functional recovery [3][4][5][6] , and some clinical trials have been performed 7,8 . However, the efficacy of NSPCs for treating SCI is currently insufficient, and unexpected serious side effects have been observed following NSPC transplantation 4,7,9 . More importantly, no direct analysis has ever been performed on the in vivo profile of NSPCs engrafted in injured spinal cord and thus the in vivo properties of engrafted cells still remain unclear.…”

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confidence: 99%

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Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells

et al. 2012

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neural stem/progenitor cell (nsPC) transplantation is a promising treatment for various neurodegenerative disorders including spinal cord injury, however, no direct analysis has ever been performed on their in vivo profile after transplantation. Here we combined bioimaging, flow-cytometric isolation and ultra-high-throughput RnA sequencing to evaluate the cellular properties of engrafted nsPCs. The acutely transplanted nsPCs had beneficial effects on spinal cord injury, particularly neuroprotection and neurohumoral secretion, whereas their in situ secretory activity differed significantly from that predicted in vitro. The RnA-sequencing of engrafted nsPCs revealed dynamic expression/splicing changes in various genes involved in cellular functions and tumour development depending on graft environments. notably, in the pathological environment, overall transcriptional activity, external signal transduction and neural differentiation of engrafted nsPCs were significantly suppressed. These results highlight the vulnerability of engrafted nsPCs to environmental force, while emphasizing the importance of in situ analysis in advancing the efficacy and safety of stem cell-based therapies.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells

et al. 2012

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“…In addition to neural replacement, NSPCs promote neurological recovery by providing trophic support and modifying the host environment to create a permissive environment for endogenous regeneration and repair [4,5,9]. Based on considerable experimental evidences, clinical trials for SCI have been performed or initiated [5,6,10], and stem cell-based therapies using NSPCs are now being translated to patients with chronic SCI [6,11,12]. However, while emerging evidence supports the therapeutic potential of NSPC transplantation for the acute and subacute phases of SCI [4,5,13], few studies have investigated NSPC transplantation for the chronic phase of SCI [14] and its therapeutic efficacy for chronic SCI thus remains controversial [3,14,15].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

et al. 2013

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The transplantation of neural stem/precursor cells (NSPCs) is a promising therapeutic strategy for many neurodegenerative disorders including spinal cord injury (SCI) because it provides for neural replacement or trophic support. This strategy is now being extended to the treatment of chronic SCI patients. However, understanding of biological properties of chronically transplanted NSPCs and their surrounding environments is limited. Here, we performed temporal analysis of injured spinal cords and demonstrated their multiphasic cellular and molecular responses. In particular, chronically injured spinal cords were growth factorenriched environments, whereas acutely injured spinal cords were enriched by neurotrophic and inflammatory factors. To determine how these environmental differences affect engrafted cells, NSPCs transplanted into acutely, subacutely, and chronically injured spinal cords were selectively isolated by flow cytometry, and their whole transcriptomes were compared by RNA sequencing. This analysis revealed that NSPCs produced many regenerative/ neurotrophic molecules irrespective of transplantation timing, and these activities were prominent in chronically transplanted NSPCs. Furthermore, chronically injured spinal cords permitted engrafted NSPCs to differentiate into neurons/oligodendrocytes and provided more neurogenic environment for NSPCs than other environments. Despite these results demonstrate that transplanted NSPCs have adequate capacity in generating neurons/oligodendrocytes and producing therapeutic molecules in chronic SCI microenvironments, they did not improve locomotor function. Our results indicate that failure in chronic transplantation is not due to the lack of therapeutic activities of engrafted NSPCs but the refractory state of chronically injured spinal cords. Environmental modulation, rather modification of transplanting cells, will be significant for successful translation of stem cell-based therapies into chronic SCI patients.

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“…[4][5][6] However, the auspicious results in animal experiments often cannot be replicated in humans. For example, the application of regeneration-facilitating olfactory ensheathing cells led to a recovery of function after an SCI in rodents, [7][8][9][10] but had no or only a poor effect on the neurological deficit in humans with SCI [11][12][13][14][15] in wellcontrolled 14 but also rather uncontrolled studies. [11][12][13]15 The main problem is the time of the treatment onset.…”

Section: Introductionmentioning

confidence: 99%

Neuronal dysfunction in chronic spinal cord injury

2010

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This review describes the changes of spinal neuronal function that occur after a motor complete spinal cord injury (cSCI) in humans. In healthy subjects, polysynaptic spinal reflex (SR) evoked by non-noxious tibial nerve stimulation consists of an early SR component and rarely a late SR component. Soon after a cSCI, SR and locomotor activity are absent. After spinal shock; however, an early SR component re-appears associated with the recovery of locomotor activity in response to appropriate peripheral afferent input. Clinical signs of spasticity take place in the following months, largely as a result of nonneuronal changes. After around 1 year, the locomotor and SR activity undergo fundamental changes, that is, the electromyographic amplitude in the leg muscles during assisted locomotion exhaust rapidly, accompanied by a shift from early to dominant late SR components. The exhaustion of locomotor activity is also observed in non-ambulatory patients with an incomplete spinal cord injury (SCI). At about 1 year after injury, in most cSCI subjects the neuronal dysfunction is fully established and remains more or less stable in the following years. It is assumed that in chronic SCI, the patient's immobility resulting in a reduced input from supraspinal and peripheral sources leads to a predominance of inhibitory drive within spinal neuronal circuitries underlying locomotor pattern and SR generation. Training of spinal interneuronal circuits including the enhancement of an appropriate afferent input might serve as an intervention to prevent neuronal dysfunction after an SCI.

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Cellular Transplants in China: Observational Study from the Largest Human Experiment in Chronic Spinal Cord Injury

Abstract: Background-In China, fetal brain tissue has been transplanted into the lesions of more than 400 patients with spinal cord injury (SCI). Anecdotal reports have been the only basis for assuming that the procedure is safe and effective.

Cited by 195 publications

References 22 publications

Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells

Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells

Therapeutic Activities of Engrafted Neural Stem/Precursor Cells Are Not Dormant in the Chronically Injured Spinal Cord

Neuronal dysfunction in chronic spinal cord injury

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