Implications of regional identity for neural stem and progenitor cell transplantation in the injured or diseased nervous system

Neural stem and progenitor cell(NSPC)transpla ntation has emerged as a promising therapeutic strategy for replacing lost neuronal populations and repairing damaged neural circuits following nervous system injury and disease.A great deal of experimental work has investigated the biology of NSPC grafting in preclinical animal models;more recently.

Nucleoside modified mRNA-lipid nanoparticles as a new delivery platform for the repair of the injured spinal cord

Spinal cord injury and treatment opportunities:The adult mammalian spinal cord has a very limited capacity for spontaneous regeneration due to various intrinsic molecular and cellular factors.Although the spinal cord neurons have the capacity to regenerate their axons,the expression of growth inhibitory factors,lack or suppression of proper guidance cues,and profound inflammatory responses do not permit successful regeneration(Khyeam et al.,2021).

Bridging the injured spinal cord with neural stem cells

Spinal cord injury （SCI） damages not only the gray matter neurons, but also the white matter axonal tracts that carry signals to and from the brain, re- suiting in permanent loss of function below injury. Neural stem cells （NSCs） have high therapeutic potential for reconstruction of the injured spinal cord since they can potentially fnrm neuronal relays to bridge functional con-nectivity between separated spinal cord segments. This requires host axonal regeneration into and connectivity with donor neurons, and axonal growth and connectivity of donor neurons to host central nervous system （CNS） circuitry. In this mini-review, we will discuss key studies that explore novel neuronal relay formation by grafting NSCs in models of SCI, with emphasis on long-distance axonal growth and connectivity of NSCs grafted into in-jured spinal cord.

Beneficial effects of BV2 cell on proliferation and neuron-differentiating of mesenchymal stem cells in the circumstance of injured PC12 cell supernatant

Objective The microglias is the representative of immune cells in the brain. It plays dual roles of both repairing and damaging in injured nervous system, and works as an inevitable component of the circumstance of injured neurons. This study was aiming at the effects of the microglias on the biological activities of mesenchymal stem cells （MSCs） in the circumstance of injured neurons. Methods MSCs were obtained by primary culture. We adopted PC12 cells （PC12） and BV2 cells （BV2） to substitute for neurons and microglias, respectively. PC12 were injured by aged Aβ1-40 and the supernatant of the injured PC12 was used to set up the circumstance of injured neurons. Transwells were used for co-culture of BV2 and MSCs, which allowed the independent detection of cells after co-culture. Immunofluorescence was used to identify MSCs and neuron-differentiating cells with CD44 and neuron specific enolase （NSE） staining, respectively. MTT assay was adopted to measure the proliferation. Results In the circumstance of both BV2 presence and injured PC 12 supernatant incubation, either the proliferation or the differentiation of MSCs reached the highest, which seemed to be contradictory, but we gave our explanations. With the BV2 co-culture, the proliferation of MSCs tend to be higher, but the neuron-differentiating MSCs were similar to those incubated without BV2 co-culture either in normal or injured in PC12 supernatant. With the incubation of injured PC12 supernatant, the neuron-differentiating cells were significantly higher than that of control （P 〈 0.05）. Conclusion In the circumstance of injured neurons, microlgias tend to promote the MSCs proliferation. Although not helpful in neuron-differentiating, microglias did not exert any negative effect either.

Transplanting neural progenitors to build a neuronal relay across the injured spinal cord

Cellular transplantation for repair of spinal cord injury is a prom- ising therapeutic strategy that includes the use of a variety of neural and non-neural cells isolated or derived from embryonic and adult tissue as well as embryonic stem cells and induced plu- ripotent stem cells. In particular, transplants of neural progenitor cells （NPCs） have been shown to limit secondary injury and scar formation and create a permissive environment in the injured spinal cord through the provision of neurotrophic molecules and growth supporting matrices that promote growth of injured host axons. Importantly, transplants of NPC are unique in their poten- tial to replace lost neural cells - including neurons, astrocytes,

Application and implications of polyethylene glycol-fusion as a novel technology to repair injured spinal cords

Conventional vs. polyethylene glycol （PEG）-fusion tech- nologies to repair severed spinal axons： Most spinal cord injuries （SCIs） involve cutor crush-severance of spinal tract axons in the central nervous system （CNS）. Clinical out- comes after CNS axonal severance is very poor because proximal segments of CNS axons lack a suitable environment for outgrowth （Kakulas, 1999; Fitch and Silver, 2008; Rowland et al., 2008; Kwon et al., 2010） and therefore do not naturally regenerate （Ramon y Caial, 1928）. Current strategies to try to increase behavioral recovery after SCI are focused on en- hancing the environment for axonal outgrowth.

Brain injury in combination with tacrolimus promotes the regeneration of injured peripheral nerves

Both brain injury and tacrolimus have been reported to promote the regeneration of injured peripheral nerves. In this study, before transection of rat sciatic nerve, moderate brain contusion was（or was not） induced. After sciatic nerve injury, tacrolimus, an immunosuppressant, was（or was not） intraperitoneally administered. At 4, 8 and 12 weeks after surgery, Masson＇s trichrome, hematoxylin-eosin, and toluidine blue staining results revealed that brain injury or tacrolimus alone or their combination alleviated gastrocnemius muscle atrophy and sciatic nerve fiber impairment on the experimental side, simultaneously improved sciatic nerve function, and increased gastrocnemius muscle wet weight on the experimental side. At 8 and 12 weeks after surgery, brain injury induction and/or tacrolimus treatment increased action potential amplitude in the sciatic nerve trunk. Horseradish peroxidase retrograde tracing revealed that the number of horseradish peroxidase-positive neurons in the anterior horn of the spinal cord was greatly increased. Brain injury in combination with tacrolimus exhibited better effects on repair of injured peripheral nerves than brain injury or tacrolimus alone. This result suggests that brain injury in combination with tacrolimus promotes repair of peripheral nerve injury.

Physical interactions between activated microglia and injured axons:do all contacts lead to phagocytosis?

Axonal injury is a pathological hallmark of both head injury and inflammatory-mediated neurological disorders,including multiple sclerosis（Schirmer et al.,2013）.Such axonal disruptions and/or disconnections typically result in proximal axonal segments that remain in continuity with the neuronal somawhile losing contact with their distal targets.

Recovery of multiply injured ascending reticular activating systems in a stroke patient

Consciousness is controlled by ular activating system （ARAS）. lower and upper parts between activation of the ascending retic- The ARAS consists mainly of the the thalamus and cerebral cortex （Edlow et al., 2012; Yeo et al., 2013; Jang et al., 2014）. Because the ARAS is composed of several neuronal circuits connecting the brainstem to the cortex. These neuronal connections begin from the reticular formation （RF） of the brainstem and the intralaminar nucleus of thalamus to the cerebral cortex （Gosseroes et al., 2011）. In addition, the ARAS system also includes several brainstem nuclei （such as dorsal raphe, locus coeruleus, pedun-culopontine nucleus, median raphe and parabrachial nucleus）, non-specific thalamic nuclei, hypothalamus, and basal forebrain （Fuller et al., 2011）.

Transplantation of human adipose tissue-derived stem cells for repair of injured spiral ganglion neurons in deaf guinea pigs

Excessive noise, ototoxic drugs, infections, autoimmune diseases, and aging can cause loss of spiral ganglion neurons, leading to permanent sensorineural hearing loss in mammals. Stem cells have been confirmed to be able to differentiate into spiral ganglion neurons. Little has been reported on adipose tissue-derived stem cells（ADSCs） for repair of injured spiral ganglion neurons. In this study, we hypothesized that transplantation of neural induced-human ADSCs（NI-h ADSCs） can repair the injured spiral ganglion neurons in guinea pigs with neomycin-induced sensorineural hearing loss. NI-h ADSCs were induced with culture medium containing basic fibroblast growth factor and forskolin and then injected to the injured cochleae. Guinea pigs that received injection of Hanks＇ balanced salt solution into the cochleae were used as controls. Hematoxylin-eosin staining showed that at 8 weeks after cell transplantation, the number of surviving spiral ganglion neurons in the cell transplantation group was significantly increased than that in the control group. Also at 8 weeks after cell transplantation, immunohistochemical staining showed that a greater number of NI-h ADSCs in the spiral ganglions were detected in the cell transplantation group than in the control group, and these NI-h ADSCs expressed neuronal markers neurofilament protein and microtubule-associated protein 2. Within 8 weeks after cell transplantation, the guinea pigs in the cell transplantation group had a gradually decreased auditory brainstem response threshold, while those in the control group had almost no response to 80 d B of clicks or pure tone burst. These findings suggest that a large amount of NI-h ADSCs migrated to the spiral ganglions, survived for a period of time, repaired the injured spiral ganglion cells, and thereby contributed to the recovery of sensorineural hearing loss in guinea pigs.

Unusual neural connection between injured cingulum and brainstem in a patient with subarachnoid hemorrhage

The human brain is known to have six cholinergic nudei （Selden et al., 1998; Nieuwenhuys et al., 2008）. The cerebral cortex obtains cholinergic innervation mainly from the basalis nucleus of Meynert （Ch 4） in the bas- al forebrain through the medial and lateral cholinergic pathways （Selden et al., 1998; Mesulam et al., 1983）. The cingulum, the neural fiber bundle connecting the basal forebrain and the medial temporal lobe, contains the medial cholinergic pathway （Selden et al., 1998; Hong and Jang, 2010）.

Electrical stimulation of cortical neurons promotes oligodendrocyte development and remyelination in the injured spinal cord

Background and early studies： Endogenous tri-potential neural stem cells （NSCs） exist in the adult mammalian central nervous system （CNS）. In the spinal cord, NSCs distribute throughout the entire cord, but exist predominately in white matter tracts. The phenotypic fate of these cells in white matter is glial, largely oligodendrocyte, but not neuronal.

Bridging large gaps in the injured spinal cord: mechanical and biochemical tissue adaptation

Incidence and consequences of spinal cord injuries： World- wide, every year 250,000-500,000 people suffer from spinal cord injury （SCI; www.who.int, 2013）. Traumatic lesions of the spinal cord lead to primary and secondary injury mechanisms, which result in axon damage, loss of signal conduction, demyelination of axons and long-lasting deficits in motor and sensory func- tion. The extent of the damage and the subsequent functional loss depend on the spinal level and the severity of the primary injury. Furthermore, pathophysiological and pathomorpholog- ical responses in acute and chronic SCI share similar but also different requirements for treatment.

Recovery of an injured corticospinal tract by subcortical peri-lesional reorganization in a patient with intracerebral hemorrhage

The corticospinal tract （CST） is a neural tract responsible for motor function in the human brain. It is mainly related to hand movements （Iang, 2014）. Therefore, recovery of an injured CST contributes to good recovery in stroke patients and a thorough knowledge of the recovery mechanism regarding an injured CST is required for successful brain rehabilitation.

Recovery of injured cingulum in a patient with traumatic brain injury

The cingulum is the neural fiber bundle that connects the basal forebrain and medial temporal lobe. The cingulum contains the medial cholinergic pathway, which originates from the basalis nucleus of Meynert in the basal forebrain. Therefore, it is important for memory function （Malykhin et al., 2008; Hong and Jang, 2010）. In the past, identification of the cingulum on conventional brain MRI has been impossible because it cannot discern the cingulum from other adjacent structures. Diffusion tensor tractography （DTT）, derived from diffusion tensor imaging （DTI）, allows three-dimensional visualization and estimation of the cingulum （Malykhin et al., 2008）.

Recovery of an injured corticospinal tract during the early stage of rehabilitation following pontine infarction

Motor weakness is a common and important sequela of stroke,and motor recovery is mostly achieved within 3 months following stroke（Jorgensen et al.,1995;Fujii and Nakada,2003）,suggesting the importance of active rehabilitation during the early stage of stroke.Many studies have reported on neurological recovery during this period,however,little is known about pontine infarction（Jang et al.,2007;Kwon and Jang,2012;Kwon

Restoration of an injured lower dorsal ascending reticular activating system in a patient with intraventricular hemorrhage

The ascending reticular activating system（ARAS）plays a key role in the control of arousal and awareness for consciousness（Paus,2000;Zeman,2001;Van der Werf et al.,2002;Weiss et al.,2007;Siposan and Aliu,2014）.It is well known that the ARAS originates from the reticular formation（RF）of the brainstem,and connects to the cerebral cortex via intralaminar to the cerebral cortex （Paus, 2000; Zeman, 2001; Van der Werf et al., 2002; Yeo et al., 2013; Jang and Kwon, 2015）. The hypothalamus is involved in the regulation of sleep and awareness which is associated with the main timekeeper of consciousness （Lin, 2000; Lin et al., 2011）.

Improvement of ataxia in a patient with cerebellar infarction by recovery of injured cortico-ponto-cerebellar tract and dentato-rubro-thalamic tract: a diffusion tensor tractography study

Coordinated movement is generated by communication between the cerebrum and cerebellum via the cerebellar peduncles (CPs). The CPs are classified into three types (superior, middle, and inferior), and each includes a variety of neural tracts. Among those tracts, the cortico-ponto-cerebellar tract (CPCT), a middle CP, is involved in motor planning and initiation of movement, while the dentato-rubro-thalamic tract (DRTT), a superior CP, is involved in motor coordination, movement timing, verbal fluency, and working memory (Kase et al., 1993.

Co-culture of astrocytes with neurons from injured brain A time-dependent dichotomy

As supportive cells for neuronal growth and development, much effort has been devoted to the role of astrocytes in the normal state. However, the effect of the astrocytes after injury remains elusive. In the present study, neurons isolated from the subventricular zone of injured neonatal rat brains were co-cultured with astrocytes. After 6 days, these astrocytes showed a mature neuron-like appearance and the number of surviving neurons, primary dendrites and total branches was significantly higher than those at 3 days. The neurons began to shrink at 9 days after co-culture with shorter and thinner processes and the number of primary dendrites and total branches was significantly reduced. These experimental findings indicate that astrocytes in the injured brain promote the development of neurons in the early stages of co-culture while these cells reversely inhibit neuronal growth and development at the later states.

Repairing the injured spinal cord: sprouting versus regeneration. Is this a realistic match?

The article by Meves and Zheng （2014） is addressing a continu- ous shift in the field of spinal cord injury （SCI） research that has occurred over the last century. Before that, the spinal cord was viewed as ＂hard wired＂ and treatment considerations were based on observations that axons in the periphery were able to regenerate, but those in the central nervous system （CNS） were not （David and Aguayo, 1981）.