Endogenous Stem Cell-Based Brain Remodeling in Mammals
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The roles of these cell populations are critical for efficient muscle regeneration, by promoting angiogenesis and maturing neovasculatures, secreting myogenic trophic factors and modulating inflammation for reduced fibrosis. Several studies have been performed to regenerate muscle tissue in situ. The roles of sustained release of insulin-like growth factor-1 and VEGF from the scaffold are mobilization and manipulation of satellite cells and inducing efficient angiogenesis for functional muscle regeneration, respectively.
In another study, a collagen-based sponge scaffold was used to treat rabbit hind limb muscle injury. At 24 weeks after implantation, the control group without scaffold showed poor structural regeneration with severe scar tissue formation at the site of injury, whereas the scaffold-implanted group showed mild focal adhesions and new muscle tissue formation. Alignment is critical for newly regenerated muscle fibers to exert normal physiological muscle function in response to nerve stimulation.
This result indicates that fabrication of muscle-specific scaffolds may be important for in situ muscle tissue regeneration. In situ tissue regeneration holds great potential to provide new therapeutic options for functional tissue regeneration. In order for this approach to be successful, stem cells need to be directed to the target sites, and appropriately guided to proliferate and differentiate into the cell type of interest within the microenvironment provided by biomaterial scaffolds.
A variety of tissue-specific biomaterials and bioactive molecules have been identified and combined to promote stem and progenitor cell mobilization. As such, the concept of in situ tissue regeneration has been demonstrated in multiple tissue systems. However, continued development of effective tissue-specific scaffolding systems that provide powerful cues for stem cell activation and recruitment is needed in order to achieve functional tissue regeneration in situ.
A better understanding of the complex interactions and pathways of the biomolecules that are involved in the targeted tissue regeneration is necessary in order to achieve effective therapeutic outcomes for translation into the clinic. Morbidity at bone graft donor sites. J Orthop Trauma ; 3 : — Volumetric muscle loss. Atala A. Engineering tissues, organs and cells.
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The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol ; 25 : — Host cell mobilization for in situ tissue regeneration. Rejuvenation Res ; 11 : — Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering.
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Buy eBook. Buy Hardcover. Buy Softcover. FAQ Policy. About this book This text highlights the endogenous regenerative potential of the central nervous system in neonates and juveniles and discusses possible ways it might be manipulated for medical purposes. Show all. The outer region is comprised of white matter and contains afferent and efferent axons arranged in tracts. Like the gray matter, white matter exhibits functional organization, with afferent tracts clustered dorsally and at the lateral periphery, and efferent tracts clustered anteriorly and medially [ , ].
The ependymal layer of the spinal cord is well known for its role in embryonic development and its function as neuroprogenitor niche. Ependymal cells divide symmetrically and migrate away from the central canal, giving rise to the different neural lineages [ 19 , ]. Postnatally, the spinal cord elongates and increases in size [ ].
The proliferation required for such growth gradually declines, leaving adult rodents and humans with little to no ependymal proliferation [ , ]. The presence of multipotent cells in the adult mammalian spinal cord was first discovered in the late s. Rat and mouse NSC were isolated and characterized in vitro.
Cultured cells were able to produce neurospheres capable of self-renewal, extended proliferation, passaging, and differentiation into the three major CNS cell types, i. It was shown later that NSC reside at the central canal and in the parenchyma of the spinal cord [ 13 , 14 ]. Although able to self-renew and generate mature oligodendrocytes, these parenchymal cells do not produce neurospheres, indicating that they are progenitors i. When spinal cord derived neurospheres are transplanted into the hippocampus they can give rise to neurons, a property that is not observed when transplanted back to the cord, and is suggestive of a non-conducive progenitor microenvironment [ 18 ].
The main constituents are ependymal cells, some of which are positive for GFAP [ , - ]. Although under physiological conditions most of these ependymal cells are quiescent, some proliferation has been observed at the dorsal tip of the central canal and ependymal cells from this region have enriched neurosphere-forming capabilities [ , , ]. Dorsal ependymal cells show a radial morphology, much like radial glia, and their processes can reach up to the white matter or even the pial surface [ , , , ].
They divide symmetrically, as they did during postnatal development [ ].
[Full text] Brain repair: cell therapy in stroke | SCCAA
A similar population and morphology has also been observed at the ventral part of the central canal, although to a lesser extent [ , , ]. It has now been shown that ependymal cells are able to generate progeny of multiple fates under physiological and pathological conditions [ , , ]. Other cells that make up the central canal are tanycytes and CSF-contacting neuron-like cells. Tanycytes, a specific subset of ependymal cells, contact blood vessels through their long basal processes and thus bridge the CSF and capillaries [ , ].
Neuron-like cells that contact the CSF through dendrite-like processes are thought to be involved in CSF homeostasis e. Pericytes that are an active part of the blood brain barrier surrounding blood vessels have also been shown to be an important source of astrocytes, implicating stem cell-like properties for these cells. These astrocytes mainly contribute to astrogliosis during injury [ ]. Central canal derived neurospheres tend to house a heterogeneous population of cells, much like neurospheres derived from other neurogenenic regions [ 34 ].
Only a small number of cells express neuronal markers such as microtubule-associated protein 2 MAP2 and DCX, which correlates with the overall preference of the cord toward oligodendrocytic and astrocytic differentiation [ 34 ]. Expression of motor neuron development transcription factors Islet1, lim1, HB9 has not been observed, reflecting the in vivo tendency towards production of GABAergic neurons [ 16 , , ]. Motor neuron differentiation can however be induced by certain morphogens, such as retinoic acid RA and Shh [ ].
Notably, neurospheres preserve information related to their rostro-caudal location, namely the expression of certain combinations of developmental genes of the Hox family [ , ]. In conclusion, the central canal of the spinal cord is mainly comprised of a heterogeneous population of ependymal cells.
Stem cell properties have mainly been attributed to ependymal cells at the dorsal tip of the central canal and to pericytes. Central Canal Niche. Cross-section through the spinal cord at lumbar level 1 Allen Developing Mouse Brain Atlas shows the location of the central canal.
Lining the lumen of the cerebrospinal fluid CSF -filled central canal is a pseudo-stratified epithelium with interspersed ependymal cells ependymocytes. Ependymal cells GFAP can be found throughout the canal and are enriched in the dorsal and ventral part latter not shown where they have a radial morphology, much like that of radial glia. Although mainly quiescent under physiological conditions, these cells become mitotically active under pathological conditions. After symmetrical division their progeny differentiate to astrocytes and oligodendrocytes. Pericytes surrounding BV not shown have been found to also contribute to the generation of astrocytes under pathological conditions, and are thus considered another form of NSC around the central canal.
Beyond the typical NSC niches referenced above it should be noted that non-typical niches have now been identified and have begun to be characterized. These non-typical niches can be further divided into those areas that are germinal neurogenic and those that are not.
Non-typical germinal regions include the hypothalamus, CVO, the meninges and the subpial layer of the cerebellum. Non-typical, non-germinal regions can be found throughout parenchyma of the cerebral cortex and spinal cord, and are mainly comprised of restricted neuroglia precursors [ 10 , 32 , 35 - 39 , - ]. Accordingly, the following paragraphs will briefly discuss selected non-typical niches in neurogenic and non-neurogenic areas.
As was the case with the typical niches, non-typical germinal regions are characterized by their inherent neurogenic capabilities, i. To be characterized as neurogenic, isolated cells should be able to give rise to secondary neurospheres in vitro whilst being able to produce all three neuronal lineages [ 36 , 37 ]. Constitutive adult neurogenesis has been identified in regions lining the third ventricle, including the hypothalamus and the CVO [ , - ].
Their ability to produce both proliferating and differentiating neurospheres in vitro strongly suggests that these areas represent germinal neurogenic NSC niches [ ]. Furthermore, it should be noted that the ECM structure and composition of the aforesaid areas strongly resemble that of the SVZ [ ]. Cells positive for nestin and DCX have also been found in the meninges of the brain and spinal cord [ - ]. Neurosphere-forming NSC have also been obtained from the cerebellum and are isolated based on their expression of the NSC marker prominin-1 CD and their lack of markers of neuronal and glial lineage markers.
Non-typical non-germinal regions are those that demonstrate proliferative properties, but are unable to induce comprehensive neurogenesis. Often these are areas within the parenchyma and consist of committed precursor cells that can self-renew and give rise only to a specific type of neuronal cell. The potential of cells in these areas to produce multipotent neurospheres is lost soon after birth [ 32 , 38 , , ].
While there are non-typical regions that may be germinal in nature rather than non-germinal, proof is still lacking.
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These putative areas include the striatum, amygdala, substantia nigra, and vagal nucleus [ 35 , ]. These cells are restricted to producing oligodendrocytes and astrocytes. The abovementioned progenitors are some of the more predominant cellular populations, yet it should be noted that parenchymal progenitors consist of an incredibly heterogeneous population, as evidenced by expression of stem cell markers.
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While crosstalk between cells populating non-typical niches under varied pathological conditions have also been begun to be highlighted [ ], much work still needs to be done to fully elucidate the function and therapeutic potential of such regions [ 10 , 35 , , ]. The paucity of viable therapeutic options stands in stark contrast to the intensity of research efforts and number of clinical trials that have been performed to date.
As of yet, there are few, if any, treatments capable of markedly improving functional recovery to levels concordant with a pre-disease state i. Therefore, the remainder of this section will seek to highlight core components of the response of adult neurogenic regions in the face of the distinctly relevant clinical entities: ischemic stroke, multiple sclerosis MS and spinal cord injury SCI.
Stroke is the one of the most common causes of death and disability worldwide. Due to an aging population, the burden will markedly increase in the coming decades and will be particularly pronounced in developing countries [ , ]. Based on this distribution, the remainder of this discussion will focus on ischemic stroke.
Cerebral ischemia and, if applicable, reperfusion cause extreme changes in the parenchymal microenvironment to include variations in oxygen O 2 concentrations, depletion of cellular energy stores e. The primary drivers of this pathogenic process stem from a crisis in energy availability and result from a reduction in O 2 and glucose [ ]. Numerous studies have now demonstrated that ischemic stroke is in fact capable of increasing neural stem cell proliferation [ , , - ].
In the SGZ, ischemia seems to act preferentially on proliferation of type 1 and 2 progenitor cells, and to a lesser extent neuroblasts [ , ]. Within the SVZ, stroke selectively increases the number of type A and C cells [ ], yet there is also data to suggest that type B cells undergo a period of transient symmetric division after stroke [ ]. Ependymal cells bordering the SVZ have also been noted to proliferate transiently after ischemic stroke [ ]. Mitotic activity appears to peak during between days post ischemia then returns to baseline levels between the th week [ , , , - ].
While maximal cell proliferation occurs on the order of days-weeks it should be noted that neuroblasts have been documented to exist for at least one year after an ischemic insult [ ]. Insulin-like factor-1 IGF-1 and granulocyte-colony stimulating factor G-CSF have also been shown to be inextricably involved in the abovementioned stroke-induced neurogenic process [ , ].
It is also important to note that the physiologic stressors of ischemia directly affect other components of the neurogenic niche and in so doing may influence neurogenesis as highlighted by studies of cerebral endothelial cells [ 27 , , ]. Inflammatory mediators have been shown to have varying effects on neural progenitor cell proliferation, migration, differentiation, survival and incorporation of newly born neurons into the CNS circuitry [ - ]. Further complicating the picture, evidence has emerged to suggest that neurotransmitters and associated excitotoxicity also mediate stroke-induced neurogenesis [ , ].
In the post-ischemic brain newly generated cells from DG and SVZ have been shown to be capable of replacing dying neurons via directed migration toward areas of damage [ ]. The neural precursors that develop, transmigrate and integrate display an innate form of pathotropism [ , ]. The experimental evidence that has been put forth hitherto clearly suggests that ischemia stimulates neurogenesis in the adult brain. Recently reports have emerged which demonstrate that the endogenous neurogenic response following experimental stroke influences the course of recovery in both short and long-term settings [ , ].
Understanding that the process of generating new neurons essentially consists of four phases: proliferation, migration, differentiation, and survival [ 89 , ] one might begin to design interventions that rationally target one or more of the aforementioned e. Specifically, Kokaia et al. Multiple sclerosis is one of the most common causes of chronic neurologic disability beginning in early to middle adult life median age of onset being 29 years of age and is characterized by a triad of inflammation, demyelination and gliosis [ - ].
MS is idiopathic in nature yet is presumed to be driven by the complex interaction of autoimmunity, genetic predisposition, and environmental associations [ , ]. MS affects approximately , people in the United States and 2. Symptoms of MS have primarily been shown to result from a disruption in the integrity of myelinated tracts in the CNS [ , ].
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More recently research has also highlighted the underappreciated involvement of gray matter in MS pathogenesis, which may be especially relevant when one considers the development of irreversible disability [ , ]. Contrasting reports have emerged with regard to the activation of the SVZ and its cellular components in MS, in both the human disease state and in animal models.
SVZ activation has been shown to be especially dependent on the temporal nature of the disease i. Such findings suggest that inflammation may be either advantageous or deleterious depending on the pathophysiologic context see Table 2. Such changes are concordant with other models of CNS injury e. Beyond the preclinical animal models, increases in SVZ activity have also been noted in humans with MS [ ]. Further, enhanced proliferation has been found at the level of the hippocampal neurogenic niche in animal models of MS.
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However, the downstream network dynamics of these progenitors appears to be altered, leading to aberrant differentiation i. Data now suggest that inflammatory components, such as infiltrating blood-born mononuclear cells, reactive CNS-resident cells i. SCI is often induced by trauma and subsequently leads to both motor and sensory deficiencies [ ]. SCI pathophysiology is marked by a pathophysiology with a complex temporospatial profile, and is characterized by three phases: acute seconds to minutes after injury , subacute hours to weeks post-injury , and chronic weeks to years post-injury [ , ].
During these phases the injured environment undergoes distinct biochemical and anatomical alterations, involving a diverse group of molecules and cells i. Factors released during the acute phase result in secondary inflammatory degeneration, the hallmark of the subacute phase. Over the course of the same period, astrocytes become reactive in a process called astrogliosis which ultimately facilitates the formation of glial scar.
This scar tissue poses a physical and chemical barrier to axonal re-growth, thus inhibiting regeneration [ - ]. On the other hand, this scar tissue aids in regeneration and repair by regulating the immune response, preventing the spread of neurotoxic factors, enabling partial reestablishment of homeostasis, and by providing neurotrophic support through enrichment of IGF, nerve growth factor NGF , BDNF and neurotrophins NT-3 [ - ]. The provision of these neuroprotective, neurogenic and regenerative cues and others is continued during the chronic phase in an effort to repair damaged axons.
This effect is however limited, due to an inhibitory microenvironment created by the glial scar and the persistence of other secondary degeneration mechanisms referenced earlier [ , ]. Interestingly, ependymal stem cells which are quiescent under physiological conditions become activated following SCI [ 39 ]. Evidence suggests a proliferative and pathotrophic NSC response. Such mitotic activation has also been observed in vitro through enhancement of neurosphere-formation capabilities post-injury[ 13 , , , ].
These proliferating ependymal cells show a transient increase in GFAP, Sb, nestin, and Pax6 expression [ 16 , , ]. The lineage potential of these transiently activated progenitors in vivo seems to be predominantly restricted to glial cells, namely astrocytes and oligodendrocytes [ , , ]. As mentioned before, pericytes are another source of astrocytes during spinal cord injury [ ]. Newly produced astrocytes function mainly in aiding the establishment of the glial scar [ , , ]. Newly produced oligodendrocytes participate in attempts to remyelinate injured axons [ ].
Unfortunately, neuronal production has not yet been reported, and may be explained by the host of powerful pro-glial cues that emanate from the spinal cord [ , , , ]; as a result functional recovery post-injury is modest at best. Cues that influence the behavior of NSC within the niche include autocrine, paracrine and endocrine factors, as well as direct cell-cell and cell-ECM contact [ 10 , , ].
A summarized overview of molecular signaling influencing NSC maintenance and neurogenesis is given in Table 1. They are produced by cells in the SVZ and induce proliferation in cells that reside in the subependymal layer lining the lateral ventricles of the forebrain [ , ]. HGF is also expressed in SVZ cells and has been shown to function as a survival factor for neuroblasts and cortical neurons while also increasing proliferation of SVZ cells [ , ]. VEGF is important for angiogenesis and hematopoiesis [ - ]. It is secreted by endothelial cells, NSC, and astrocytes [ ].
VEGF exerts indirect effects on NSC and neurogenesis by inducing angiogenesis thereby providing structural and trophic support [ ]. It also operates directly via the promotion of proliferation and maintenance of NSC and neurogenesis [ , ]. Furthermore, VEGF has been shown to be neuroprotective during disease and injury [ , ].
IGF-1 is expressed in various areas of the CNS, including hippocampus, olfactory bulbs, and cerebellum [ , ]. Multiple knockout studies have indicated that IGF-1 is needed for maintaining proliferation and stem cell characteristics [ , ]. PEGF was first identified as a factor that induces differentiation of retinoblastoma cells into a neuronal phenotype [ , ].
It has been found to be expressed by retinal cells, adipocytes and hepatocytes, and also endothelial and ependymal cells in the adult brain [ ]. Although NSC do not express these factors themselves, they are responsive to them. It has no effect on survival, but increases NSC self-renewal and activates quiescent subependymal cells [ ].
It is believed that PEGF function is dependent on Notch signaling and keeps cells undifferentiated through upregulation of Hes1, Hes5, and Sox2 [ , ]. Wnt signaling pathways are major regulators of stem cell activity in the developing and adult brain, where it functions in both NSC maintenance and neurogenesis [ , - ]. Wnt3, for instance, is secreted by astrocytes and induces NSC proliferation and neurogenesis [ ].
Wbt7b is regulated by retinoic acid and can expand the number of proliferating cells [ , ]. However, when factors such as homeodomain interacting protein kinase 1 HipK1 are upregulated in the SVZ, the same pathway can induce differentiation [ ]. Furthermore, in pathological conditions such as stroke and hypoxia, Wnt signaling has been shown to drive neurogenesis through NSC proliferation and differentiation. Interestingly, these activated cells divide symmetrically leading to NSC expansion, as opposed to the asymmetrical division that normally takes place in the subendymal zone [ , ].
They inhibit proliferation of neuroblasts while blocking neurogenesis and favoring gliogenesis [ ].