Pluripotent Stem Cells for Spinal Cord Injury Repair

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Beatriz Fernández-Muñoz	+ 4151 word(s)	4151	2021-11-30 04:19:33	\|
2	format correct	Conner Chen	Meta information modification	4151	2021-12-10 09:53:46	\|

This entry is adapted from the peer-reviewed paper 10.3390/cells10123334

Spinal cord injury (SCI) is a devastating condition of the central nervous system that strongly reduces the patient’s quality of life and has large financial costs for the healthcare system. Cell therapy has shown considerable therapeutic potential for SCI treatment in different animal models. Although many different cell types have been investigated with the goal of promoting repair and recovery from injury, stem cells appear to be the most promising.

tetraplegia cell therapy animal models

1. Embryonic Stem Cells for SCI Repair

During the last two decades, numerous studies have explored whether the use of ESC-derived cells has some benefit for SCI repair (Table 1). Many studies have differentiated ESC to neural cells with stem properties and have called them neural stem, neural progenitor or neural precursor cells. Since these terms are sometimes used interchangeably, in this review, we only use the term neural stem cells (NSC) to simplify. McDonald and colleagues ^[1] were the first to evaluate murine ESC differentiated to the neural stem lineage to promote recovery after SCI. Cells transplanted into a rat model of subacute SCI differentiated into astrocytes, oligodendrocytes, and neurons. The preliminary results were encouraging, and rats displayed locomotor recovery by hindlimb weight support and partial hindlimb coordination. However, transplanted cells were poorly characterized—a fact that limited the interpretation of the results. Another pioneering study transplanted murine ESC into the injured area of mice with subacute SCI 10 days post-injury. Compared to the control group, mice transplanted with NSC showed significant score improvements in three behavioral tests. Additionally, neurons and oligodendrocytes were detected in the graft areas; however, few axons penetrated or sprouted from the grafts ^[2]. These results were encouraging, but the NSC used were poorly characterized, only considering the expression of nestin, hindering the replication of these results.

ESC-derived neurospheres (NS) containing NSC have also been used for SCI cell therapies. To evaluate its efficacy for SCI repair, Kumagai and colleagues ^[3] compared the grafting of primary NS (from a single cell suspension of murine EB-derived neurospheres) versus secondary NS (obtained by secondary culture of dissociated primary NS) in subacute SCI (9 days post-injury). Surprisingly, gliogenic secondary NS, but not neurogenic primary NS, promoted axonal growth, remyelination and angiogenesis, and resulted in significant locomotor functional recovery after SCI. In another study, NSC from human ESC, embedded in fibrin matrices containing a growth factor cocktail, were grafted into the injured spinal cord in rats. After complete spinal cord transection, ESC-derived NSC formed large numbers of projections from the injury site. The derived axons expressed the presynaptic marker synatophysin, and the graft-derived axons were myelinated by host oligodendrocytes, suggesting integration with host cells ^[4].

Another strategy applied for SCI repair has been the use of ESC-derived cells with forced expression of specific factors. For example, Butenschön and colleagues reported the effect of mouse ESC–NSC overexpressing BDNF, isolated by magnetic and fluorescent-activated cell sorting, in subacute SCI. Recovery of motor function was observed only in animals transplanted with SSEA-1-/PSAN-CAM+ cells overexpressing BDNF, but not in control NSC ^[5]. Another study ^[6] used substrate adherent ESC-derived neural aggregates constitutively overexpressing the neural cell adhesion molecule L1. Neural aggregates-L1 cells transplanted 3 days after injury rescued endogenous spinal cord interneurons and motor neurons, and promoted the regrowth of catecholaminergic nerve fibers distal to the lesion site.

In general, the results reported using mouse and human NSC differentiated from ESC could be considered positive. In fact, at least one clinical trial has been launched in 2021 with ESC–NSC for cervical sub-acute SCI (NCT04812431) (Table 2). In this trial sponsored by S. Biomedics Co (Seoul, Republic of Korea), two to six subjects with damage at the C4-C7 level will be recruited and administered ESC–NSC PSA-NCAM positive, to evaluate safety and exploratory efficacy. The cells will be administered intrathecally, in five areas, and all subjects will be subjected to a follow-up study after a period of 1 year and 5 months. This clinical trial has been launched very recently and no patient has yet been recruited, but the results obtained from this study could be valuable to determine whether ESC-derived NSC are safe. There is always a potential safety risk when transplanting cells that are not terminally differentiated, and often poorly characterized. Potential ectopic spreading (dissemination over extended distances) is of concern. The high pressure used during NSC injection could force cell egress from the injury site and favor remote cell dissemination. However, the use of another injection method with lower pressure did not show dissemination in monkeys ^[7]^[8]. In addition, there are differences between animal models of SCI (mainly rat) and human SCI, including open versus closed lesions, and the fact that the human vestigial central canal is functionally closed in most individuals by the second decade of life. These dissimilarities would suggest that the risk of biodistribution would be lower in humans ^[7]^[8]. Clearly, studies are warranted to resolve these issues.

Assuming that all injuries in the spinal cord are created equally, some investigators have chosen to transplant cells that are further along the differentiation path than NSC, including oligodendrocytes, astrocytes, and a variety of neuronal-type cells. This assumption entails a significant speculation considering the multiple tracks involved and the different causes of trauma in SCI. The obvious advantages of this approach are the fact that the tumorigenic potential will probably decrease, and that it allows some degree of control over the final cell types that are grafted, albeit at the expense of having to speculate the type of cells each particular lesion needs.

In this regard, the first study to analyze the therapeutic effect of more differentiated cells used human ESC-oligodendrocyte progenitor cells (OPC) in a rat model of spinal cord injury ^[9]. After grafting these OPC into rats with subacute and chronic injuries (7 days or 10 months after injury, respectively), only those animals that received the transplant in the subacute phase showed enhanced remyelination and improved motor function. The same group ^[10] tested the therapeutic effect of human ESC–OPC using a moderate and severe contusive spinal cord injury model. The severe contusion induced extensive demyelination, and the transplantation of human ESC–OPC showed robust remyelination. Based on the efficacy results shown in the preclinical studies and on the extensive safety analyses ^[11], the Food and Drug Administration (FDA) approved a phase I clinical trial in 2009 (NCT01217008) sponsored by Geron Corporation (Menlo Park, CA, USA), aimed at analyzing the safety of human ESC–OPC (GRNOPC1) ^[9]^[10]^[12]. The trial was halted for reasons other than those related to safety or efficacy. Full data on the outcome of these experiments have not yet been published ^[11], but some information was shared in various scientific forums. It was reported that no serious adverse events were detected in the first five patients that received GRNOPC1 at a low dose (2 million cells). The only side effects observed were related to the immunosuppressive regime used (tacrolimus). No changes in the spinal cord or neurological condition were found, and while the cells used were allogeneic, there was no apparent evidence of immunological rejection. At the end of 2013, Geron’s Stem Cell Program was taken over by Asterias Biotherapeutics, Inc. (Fremont, CA, USA), and GRNOPC1 was renamed AST-OPC1. The new strategy advanced by Asterias was a dose-escalating trial to treat three patients with cervical injuries using a low dose of cells, and subsequently to treat more patients with higher doses to assess whether the therapy can restore any sensory and/or motor function in the trunk and/or limbs ^[12]. In August 2015, with financial support from the California Institute for Regenerative Medicine, as a strategic partnership award, Asterias relaunched a phase I/II open-label clinical trial (NCT 02302157), and the initial low-dose (2 million cells) safety cohort, which included three patients. In subsequent phases, they tested sequentially increasing doses of 10 to 20 million cells in one or two injections, to be administered 21 to 42 days after injury in 22 patients with subacute, C-5 to C-7, neurologically complete SCI. Preclinical efficacy and safety data in a nude rat model of cervical SCI showed improved locomotor performance, using the automated TreadScan system, when human AST-OPC1 was administered directly into the cervical spinal cord in subacute injury, and no adverse effects were reported ^[13]. Since 2019, when BioTime acquired Asterias, creating the cell therapy company Lineage Cell Therapeutics, manufacturing has been completely transferred to the company’s current Good Manufacturing Practice (cGMP) facility in Israel, where key process improvements have been developed and implemented. According to the available information from the company, after one year, 96% of the treated patients reported improved motor function (one-third of the patients gained two levels of motor function and two-thirds gained one level) ^[14]^[15].

Human ESC–OPC have also been tested in a cervical rat model, rather than the more commonly used thoracic model ^[16]. Grafted cells attenuated the severity of the injury and improved the recovery of forelimb function and range of motion. The histological effects of transplantation included robust white and gray matter sparing at the injury epicenter, and specifically, preservation of motor neurons that correlated with movement recovery. They also identified gene expression changes supporting the histological and functional improvement. Another group assayed the effect of allogeneic ESC–OPC transplantation in the subacute phase of cervical SCI in marmosets, a non-human primate. The grafted cells survived and showed the potential to differentiate into the three neural lineages in the injured spinal cord environment. Derived oligodendrocytes contributed to the remyelination of axons, and synaptic connections between grafted green fluorescent protein (GFP)-positive neurons and host cells were observed. These facts support the motor functional recovery observed. In addition, regarding safety, the results show that the marmoset recipient lymphocytes did not respond to allogeneic ESC-derived cells, and no signs of tumorigenicity after transplantation were observed ^[17].

Mouse ESC-derived glial progenitors positive for the nerve glial antigen 2 (NG2) marker and matrix metalloproteinase 9 have also been tested. These cells could penetrate the glial scar formed after subacute SCI. In addition, the axons of these cells grew over long distances (>10 mm) with a preference to traverse white matter rather than gray matter. These facts support the notion that the expression of chondroitin sulfate proteoglycan in the injury scar is an impediment to regeneration, and that NG2-positive ESC-derived glial progenitors can breach this barrier and promote axon growth ^[18].

Allodynia and hyperalgesia are the two forms of spontaneous neuropathic pain that affect approximately 50% of SCI patients and persist over time, complicating the rehabilitation and decreasing the quality of life. Hwang and colleagues, in an effort to address this problem, transplanted ESC-derived spinal GABAergic neural precursor, 3 weeks post-injury. They observed a reduction in neuropathic pain in injured animals 2 weeks post-transplantation, and the effect persisted for up to 7 more weeks, although locomotor function did not improve ^[19]. Fandel and colleagues also showed that human ESC-derived inhibitory interneuron precursors were able to substantially ameliorate neuropathic pain and improve bladder function, although they did not find a noticeable locomotor recovery ^[20].

In this context, other groups have tested a combination of cells. For example, Niapour and colleagues transplanted a combination of Schawnn cells isolated from the sciatic nerve and human ESC–NSC, with the goal of improving the differentiation of NSC after transplantation, into a subacute SCI rat model at thoracic level ^[21]. The presence of Schawnn cells in the human ESC–NSC + Schawnn cells-transplanted group was found to significantly boost the proportion of neuronal markers (TUJ1 and MAP2). Although enhanced locomotor function recovery was observed in all groups (NSC, Schawnn cells, NSC + Schawnn cells), a synergistic effect was promoted by the co-transplantation of human ESC–NSC and Schawnn cells. Animals receiving co-transplants established a better state, as assessed by the BBB functional test at week 5. Similarly, Salehi and co-workers ^[22] used the co-transplantation of ESC-derived motor neurons and OEC in a subacute thoracic SCI in rats, using the Vanicky’s method for SCI ^[23], which may not be sufficiently precise and reproducible. The co-transplantation of ESC-derived motor neurons and OEC also had a synergistic effect in promoting neural regeneration and survival, but the recovery of hindlimb function was not significantly enhanced by co-transplantation. Taken together, these three studies—while still far from explaining the mechanism of action responsible for the observed recovery in transplanted animals—highlight the potential of using a combination of different, and more differentiated, cell types for transplantation. Nevertheless, the specific combination (and percentage) of each cell type remains to be determined.

2. iPSC for SCI Repair

iPSC are artificially induced pluripotent stem cells from adult somatic cells, overcoming the ethical problems associated with the use of embryonic stem cells. Several groups, including our own, have evaluated the transplant of iPSC-derived cells in preclinical models of SCI. Similarly to ESC, many researches chose iPSC-derived NSC to treat SCI. For example, Fujimoto and colleagues showed that iPSC–NSC have a therapeutic potential comparable with NSC isolated from human fetal spinal cord in a mouse acute model of thoracic SCI. Furthermore, the iPSC–NSC group showed enhanced remyelination and axon regeneration, and supported the survival of endogenous neurons. Motor function recovery was promoted through the reconstruction of the corticospinal tract, restoring disrupted neuronal circuitry in a relay manner. In addition, these authors used specific cell ablation protocols with diphtheria toxin. After the recovery of motor function was observed, diphtheria toxin was administered to the transplanted animals and, as expected, the condition of the animals worsened, demonstrating that recovery was attributed to transplanted cells ^[24].

Romanyuk and co-workers also reported the beneficial effects of human iPSC–NSC in a rat model using balloon-induced acute SCI at the thoracic level ^[25]. Cells were transplanted in the acute phase and showed robust survival, and migrated and partially filled the lesion cavity, resulting in significant motor improvement from the second week after transplantation. Similarly, human iPSC–NSC were transplanted into a rat model using the same conditions with the intention of testing the administration route. Cells were transplanted intrathecal and intraspinally, finding, in both cases, that the animals improved locomotor function ^[26]. Another, more recent study reported positive results. Kong and coworkers showed that human iPSC–NSC reduced pro-inflammatory cytokine levels after SCI, evidenced by the reduced glial and fibrotic scar formation, in an acute mouse model of thoracic SCI. The cells, furthermore, promoted the recovery of limb function ^[27].

Nevertheless, motor recovery is not always achieved in iPSC-derived cell transplantation studies for SCI repair. Many studies have shown that transplanted cells survived and even differentiated into the three lineages in the host tissue, but this does not always imply integration or locomotor improvement. For example, Pomeshchik and colleagues ^[28] performed thoracic contusions in mice and transplanted human iPSC–NSC 7 days after injury (subacute). Motor function was assessed at 6 weeks post-injury by BMS and Catwalk gait analysis. The authors concluded that transplanted human iPSC–NSC had no effect on the size of the lesion and did not promote behavioral recovery after SCI. Additionally, human iPSC–NSC showed limited long-term survival. The authors attributed these results to an insufficient immunosuppression dose.

In another fashion, the use of regionally specific iPSC–NSC has also been attempted. Kajikawa and coworkers hypothesized that, given that there are subtypes of NSC regarding their regional identity, spinal cord-type NSC would be the most adequate to inject into SCI for regenerative purposes. They injected forebrain and spinal cord-type iPSC–NSC into a mouse acute model of SCI. Both types of NSC were grafted onto host tissue; however, only the spinal cord type showed connection with the corticospinal tract of the host and, moreover, resulted in recovery of motor function ^[29].

The level at which the SCI is located is an important factor to take into account in terms of achieving recovery in motor function, as cervical lesions entail a much more severe impairment than thoracic ones. The chronicity is also a relevant factor that should be considered. The maturation of the glial scar surrounding the lesion around 2–3 weeks post-injury is well documented to become a barrier to axonal regrowth and tissue regeneration due to the inhibitory environment within the lesion ^[30]^[31]. Thus, the moment in which the cell treatment is applied is also critical to the outcome.

With the aim of modeling the clinically relevant condition of chronic cervical contusion, Nutt and coworkers tested human caudalized iPSC–NSC in a rat cervical model of chronic SCI. They chose to use the Forelimb Reaching Test (FRT), a very stringent test that offers advantages over others, as it provides a more objective behavioral comparison between and within treatment groups ^[32]. Human iPSC–NSC were delivered to a unilateral cervical contusion injury generated on the dominant forelimb side. Grafted human iPSC–NSC differentiated into neurons, astrocytes, and oligodendrocytes. In addition, mature and specific neuronal subtypes were generated and projections were observed surrounding host neurons, suggesting integration with host networks ^[33]. However, the study fell short of producing significant functional recovery.

In a different approach, some investigators have opted to use scaffold structures as a cell delivery platform, and to expedite cell differentiation and tissue formation. As an example, Lu and colleagues ^[34] embedded human iPSC–NSC in fibrin matrices containing a growth factor cocktail in cervical subacute models of SCI, both in rats and mice. They found that host serotonergic axons penetrated human iPSC–NSC grafts and expressed the terminal presynaptic marker synaptophysin. Reticulospinal motor axons also penetrated human iPSC–NSC grafts, demonstrating that reciprocal connections had formed from host-to-graft and graft-to-host. However, collagenous rifts, which axons were unable to cross, were present within the centers of most grafts, and the evaluation of locomotor function found no recovery in this regard. More recently, Ruzicka and coworkers used laminin-coated polymer-based hydrogels containing two sizes of pores: large-sized ones, suitable for cell adhesion and expansion, and small-sized pores, which enabled nutrient diffusion. These scaffolds, loaded with iPSC–NSC, were transplanted into a rat model of chronic SCI. Notably, the constructs integrated in the host tissue, but they failed in restoring motor function ^[35].

Combinatorial therapies have also been applied. Some studies have chosen to condition cells with small molecules to improve their performance in vivo. For example, Shiga and collaborators conditioned iPSC–NSC with enzymatically inactive tissue-type plasminogen activator (EI-tPA), prior to grafting into an acute rat model with severe thoracic SCI. EI-tPA interacts with cellular receptors to mediate changes in cell physiology potentially relevant to the challenges of stem cell therapy; it is neuro-protective to cortical neurons, and promotes neurite outgrowth in neurons and neuron-like cells by activating cell-signaling factors, such as c-Src and ERK1/2. Furthermore, it may regulate innate immunity by suppressing toll-like receptor responses. Notably, they found that the cells differentiated, acquired markers of motor neuron maturation, and extended βIII-tubulin-positive axons several spinal segments below the lesion. Furthermore, they observed a decrease in muscle atrophy, and animals had significantly improved motor function, without exacerbating pain ^[36]. Bonilla and coworkers combined human iPSC–NSC, MSC and a pH-responsive polyacetal–curcumin nanoconjugate (PA-C) that allowed the sustained release of curcumin to treat thoracic SCI in a rat subacute model. This molecule reduces neuroinflammation after SCI by suppressing the TLR4/NF-κB signaling pathway. Furthermore, given the antioxidant and immunomodulatory properties of curcumin, they hypothesized that PA-C pre-treatment could protect iPSC–NSC exposed to cytotoxic doses of hydrogen peroxide. They reported beneficial outcomes, such as the preservation of neuronal fibers and the reduction of scar tissue. Unfortunately, these significant results did not translate into locomotor recovery ^[37].

In the last few decades, SCI in the elderly population has increased substantially due to life expectancy ^[38]^[39]. In this regard, some studies have arisen to model the condition ^[40]. Our own laboratory has recently published a study that models chronic cervical SCI in aged rats that were further treated with iPSC–NSC. The animals experimented on showed very high mortality rates, both at SCI induction and with iPSC–NSC treatment, due to their age-related frailty, even though we found that the transplanted cells survived for one month in the spinal cord of aged animals, and no signs of tumor development or adverse reactions were noted. Nevertheless, no locomotor improvement was observed after transplantation ^[41].

An important issue at stake is the safety of iPSC-derived cells, which must be rigorously evaluated before they enter the clinic ^[42]. Several studies have been published with the aim of finding a process to try to remove tumorigenic cells before or after transplantation. Many of them have been performed by the Okano Laboratory group. They prescreened murine iPSC-derived cells prior to transplantation, and tested their safety in intact mouse intact cords and their efficacy in a subacute contusion injury model ^[43]. In this study, iPSC colonies were prescreened prior to transplantation, and “safe” colonies properly differentiated and promoted locomotor recovery, while “unsafe” colonies generated teratomas and failed to promote long-lasting locomotor recovery. Given the previous experience of the group with ESC–NSC transplant ^[3], where secondary NS provided therapeutic benefits, they transplanted cells isolated from both primary and secondary NS. iPSC–secondary NS contributed to remyelination and induced the axonal regrowth of host serotonergic fibers, which resulted in locomotor function recovery. In a subsequent study, they tested human iPSC–secondary and tertiary NS ^[44]. As expected, the grafted cells differentiated and the animals showed significant locomotor recovery, supported by synapse formation between human iPSC-NS-derived neurons and host mouse neurons, the expression of neurotrophic factors, angiogenesis, axonal regrowth, and increased amounts of myelin in the injured area. Kobayashi and coworkers even transplanted iPSC–NSC into a primate model, which had positive results in terms of motor recovery and safety ^[45]. Nevertheless, in a long-term study with mice, the authors found that the grafted animals, which had initially recovered, gradually lost their motor function and developed tumors. Moreover, these tumors consisted of nestin-positive undifferentiated neural cells, and showed altered expressions of genes involved in the epithelial–mesenchymal transition, which may have promoted tumor invasion and the progression of grafted cells ^[46]. Fuhrmann and coworkers ^[47] developed an injectable hydrogel comprised of hyaluronan and methylcellulose to enhance the survival and differentiation of human iPS-OPC, and injected it in a subacute rat model of SCI. The transplanted animals formed teratomas; however, the hydrogel reduced the incidence to 50% compared to the group injected with medium. Okubo et al., 2016 tried to prevent tumorigenesis by pretreating human iPSC–NSC with γ-secretase inhibitor, which inhibits Notch signaling. This treatment promotes differentiation to neurons, resulting in improved motor function in subacute and chronic SCI models ^[48]^[49]. On the other hand, Itakura and coworkers ^[50] tested the efficacy of the inducible caspase9 gene in avoiding the tumorigenic transformation of human iPSC–NSC in vivo. They injected cells with a tumor formation tendency into a thoracic NOD-SCID mouse subacute model. iPSC–NSC were transplanted at the lesion epicenter and, once tumor formation was observed, a small-molecule chemical inducer of dimerization (CID) was administered to induce the apoptosis of the injected cells, and all grafted cells retreated. Before tumor formation, they found that cells were able to differentiate, and that mice showed improved hindlimb motor function until week 4 after transplantation, when tumors started appearing. In those animals on which the grafted cells were ablated, the motor function declined, although it remained slightly better than in sham mice.

Recently, Chow and collaborators generated canine iPSC–NSC and transplanted them into pet dogs with chronic thoracic SCI after a traumatic accident. Observation via MRI did not show any changes in the lesion size or the glial scar of the animals. No adverse effects were observed either, demonstrating the safety of administering iPSC-derived NSC in dogs with follow-up for 6–12 months, particularly with respect to tumor formation at the injection site. However, the animals did not show an improvement in motor function ^[51].

Similarly to the progress made with human ESC, various groups have tried transplanting more differentiated human iPSC-derived cells. Hayashi and coworkers ^[52] used mouse iPSC to form neurospheres, which were subsequently differentiated to astrocytes. iPSC-derived astrocytes were transplanted into rats with thoracic SCI in the subacute phase of SCI. Although three different tests were used for locomotor evaluation (BBB test, inclined-plane test and SCANET MV-40 (Melquest), no significant improvement was detected in relation to the control group. Nevertheless, an increase in sensitivity to mechanical stimulus was described. Interestingly, Salewski and colleagues found that primitive NSC (incompletely committed to the neural lineage and still expressing some pluripotency markers) generated tumors after injection. By contrast, definitive NSC (committed to the neural lineage and with no expression of pluripotency markers) did not generate tumors ^[53]. These data indicate the relevance of transplanting more differentiated cells.

Using an induced thoracic contusion in NOD-SCID mice, Kawabata and collaborators grafted human iPSC–OPC into the lesion epicenter (subacute phase). The authors found that the grafted human iPSC–OPC contributed to remyelination, promoted axonal growth, and contributed to synapse formation with host mouse neurons, leading to enhanced functional recovery after SCI. However, when comparing the results with a previous study using human iPSC–NSC, they found no therapeutic differences in hindlimb motor function ^[54]. Recently, Patil and coworkers transplanted iPSC–pre-OPC into a model of chronic SCI. Their study consisted of ablating the glial scar to eliminate the hostile environment prior to cell transplantation. As a result, the lesion cavity was significantly reduced; nevertheless, no functional recovery was achieved.

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Beatriz Fernández-Muñoz

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1. Embryonic Stem Cells for SCI Repair

2. iPSC for SCI Repair

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