Potential Benefits of Stem Cell Research for Alzheimer's Patients and Their Families.

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• Open Access
• Published: 12 May 2017

Alzheimer's disease, dementia, and stem jail cell therapy

Stalk Cell Enquiry & Therapy volume 8, Article number:111 (2017) Cite this article

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Abstract

Alzheimer'south disease (AD) represents arguably the well-nigh significant social, economical, and medical crisis of our time. Characterized past progressive neurodegenerative pathology, AD is offset and foremost a condition of neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells is therefore a rational therapeutic strategy. This review will focus on recent advances in stem cell therapies utilizing creature models of Advertisement, as well equally detailing the human clinical trials of stalk jail cell therapies for Advert that are currently undergoing development.

Background

Approximately 50 one thousand thousand people live with dementia, with the estimated global cost of care being Us$818 billion. As historic period is the predominant risk factor and national demographics are rapidly ageing, this figure is set to rise to 132 million people past 2050 [1]. Dementia is a fatal clinical disorder characterised past amnesia, progressive cerebral damage, disorientation, behavioural disturbance, and loss of daily function; Alzheimer's illness (AD) is the most common associated pathology. Information technology can be argued that dementia is ane of the about meaning social, economic, and medical challenges of our time.

Less than five% of AD cases are familial, caused by highly penetrant autosomal mutations of the PSEN1, PSEN2, and, less frequently, APP genes. The majority of AD cases are tardily onset and sporadic, with established risk factors across age including cardiovascular disease, depression education, low, and the apolipoprotein-E4 (ApoE4) cistron. Sporadic Advertizing is appropriately of multifactorial origins, driven in role past a complex genetic contour and in part by interacting and intersecting environmental exposures.

It should therefore not exist surprising that AD pathology is diverse. 4 core features can be discerned. Firstly, tau, an intracellular microtubule-associated protein within neurons important for structural support and axonal transport, becomes hyperphosphorylated, leading to microtubule collapse and aggregation into neurofibrillary tangles. Secondly, sequential cleavage of the APP protein by β- and γ-secretase enzymes leads to extracellular accumulation and aggregation of beta amyloid (Aβ) protein fragments, visible every bit amyloid plaques in the AD encephalon. Many pharmacological approaches accept attempted to promote amyloid clearance by vaccination [2] and decrease production via secretase inhibition [three]. Even so, results from human being clinical trials bespeak that amyloid pathology does not correlate with clinical symptoms and therefore may not be a therapeutically relevant target. The third core characteristic of Ad is the presence of activated microglia, the resident macrophages of the cardinal nervous organization (CNS), and found in close clan with amyloid plaques. Present from the early on stages of the disease, their numbers then pass up in the avant-garde AD brain. Activated microglia produce cytokines, such equally tumour necrosis cistron (TNF)-α, interleukin (IL)-1β, and nitric oxide (NO), that may exacerbate or benumb neuroinflammation [4]. Mass neuronal and synaptic loss represents the forth core characteristic of Advert and is the closest correlate of cognitive decline in early Advertising [5]. Advertizement-related neurodegeneration in the temporal lobe follows a singled-out pattern. The entorhinal cortex is get-go affected, then progressing to the subiculum and CA1 hippocampal subregion and basal forebrain networks. Atrophy of these encephalon regions and the hippocampus overall co-vary with verbal episodic memory deficits in Advertising patients [5]. In later stages of the disease neurodegeneration spreads throughout the temporal lobes, eventually affecting most cortical layers. The precise temporal sequencing of this complex admixture of pathologies in human sporadic Advert is the subject of intense debate.

Due to the progressive nature of AD, if a stalk cell therapy is to be successful it must target a well-divers clinical subset of patients. Given the involvement of hippocampal circuitry in the early phases of the disease, we suggest this region equally a potential therapeutic target. At that place is at present an enormous global demand for new effective therapies that not only halt progression simply also contrary symptoms. In this review, we argue that a potentially constructive strategy is to target the biological feature most closely tied to symptoms, namely neurosynaptic loss. Specifically, we focus on recent advances in jail cell-based therapies that aim at repopulation or regeneration of degenerating neuronal networks in Advertizement.

Stalk cell classes

An important stride in developing any stalk cell therapy is to cull the appropriate jail cell source. The most commonly utilized cells in recent AD studies are embryonic stalk cells (ESCs), mesenchymal stalk cells (MSCs), brain-derived neural stem cells (NSCs), and induced pluripotent stalk cells (iPSCs). ESCs are derived from the inner cell mass of the developing blastocyst (at embryonic day 5 to vi) and are classified equally pluripotent because they possess the ability to generate prison cell types from the ectodermal, mesodermal, and endodermal germ layers. MSCs are involved in the development of mesenchymal tissue types and can exist harvested from umbilical cord blood (UCB-MSCs) or Wharton'south jelly, and as well remain nowadays in several adult stalk jail cell niches including os marrow and adipose tissue. Classified every bit multipotent, MSCs are able to generate multiple jail cell types that share a mutual embryonic origin, namely the mesodermal germ layer. Despite this, phenotypic expression and the differentiation potential of MSCs can vary according to the tissue of origin [6]. Similarly multipotent, NSCs are responsible for the generation of all neural cell types during development. While besides present in the adult encephalon, they are restricted to the detached neurogenic niches of the subventricular zone and the granular layer of the dentate gyrus in the hippocampus. Finally, iPSCs are derived from mature somatic cells in vitro, commonly adult dermal fibroblasts, and are genetically modified by modest molecule treatment or viral vector-delivered transcription factor upregulation to get pluripotent and ESC-like in phenotype and differentiation capacity [seven].

Endogenous repair

There are several theoretical approaches to the design of a stem cell therapeutic strategy for early Advertizement. One is to target upregulation of resident NSC niches within the developed brain, in effect stimulating adult hippocampal neurogenesis to compensate for neurodegeneration. Adult hippocampal neurogenesis may have a key role in learning and memory, then promoting this process may help counter the amnestic symptoms of early Advertising. One selection has been to upregulate (pharmacologically or with cistron therapy) those growth factors known to positively regulate neurogenesis, including brain-derived neurotrophic factor (BDNF), insulin growth gene-ane (IGF-ane), nerve growth factor (NGF), and vascular endothelial growth factor (VEGF) [8].

This approach is, notwithstanding, complicated past several quantitative challenges. Firstly, the rate of hippocampal neurogenesis decreases with historic period in humans, with an estimated 800 new neurons produced daily in adulthood declining to ~100 in late life under disease-free conditions. Since the best estimates suggest neuronal number is stable in normal ageing, this is therefore the minimum required to achieve neuronal equilibrium because of rapid neuronal turnover. Secondly, in Ad there is mass loss of hippocampal neurons. In the dentate gyrus the loss is estimated at ~one One thousand, and in CA1 the loss is estimated at ~5 meg. Hence, to compensate for AD at that place would demand to be an gild-fold increment in hippocampal neurogenesis to normalise dentate gyrus numbers. Furthermore, developed hippocampal neurogenesis has no effect whatever on CA1 neurons and so the chief neuronal deficit in early AD is unaddressed. Tertiary, this approach must account for the effect of Advertizement pathology on neurogenesis, for which in that location is alien evidence from animal studies [9, ten]. Overall, endogenous strategies for neuronal repair in early on AD lack potency and miss one of the main neuronal targets.

Exogenous cell therapy

Exogenous prison cell therapies aim to restore degenerate neuronal networks, and consequently cognitive office, through the introduction of stalk cells. These stem cells may be used as a cellular delivery arrangement, utilizing a paracrine "bystander" machinery through either native or induced production of neuroprotective growth factors. Alternatively, therapeutic restoration may occur through differentiation and participation of the stalk cells in repopulating degenerate neuronal circuits. This is a finely counterbalanced, complex, and multistep procedure. Each course of stem cells has dissimilar propensities to achieve these approaches, as briefly reviewed hither. Details of recent Advertisement model stem prison cell transplantation studies featured in this review are summarized in Table ane.

Table i Advertisement rodent model stem cell transplantation studies in the concluding 5 years

Full size table

ESCs

While some ESC transplantation studies accept shown a capacity to restore cognitive role in rodent models of brain injury [xi], their clinical translation has been limited. This is in part due to their pluripotent nature, equally transplantation of undifferentiated ESCs presents an inherent risk of uncontrolled cell growth and tumour formation [12]. In vitro pre-differentiation of ESCs into NSCs circumvents some of this risk, generating predominantly cholinergic neurons and inducing improvements in spatial memory performance after transplantation into an Advertizing rodent model [13]. More recently, i study reported the stable generation of cholinergic neuronal populations from human ESCs which, following transplantation, were able to functionally integrate into hippocampal neuronal circuitry [14]. In 2013, another written report reported the conversion of ESCs into medial ganglionic eminence-like progenitor cells—a transient stem cell type nowadays in the developing encephalon. Following transplantation into a murine brain injury model, these cells were capable of maturing into both GABAergic and cholinergic neuronal subtypes and synaptically integrating with host neuronal circuits, leading to improvements in impaired spatial retentiveness and learning [xv]. Despite ongoing preclinical studies, at that place are inherent upstanding and immunogenic limitations to using allogeneic donor cells that significantly hamper the clinical translation of ESC-based therapies.

NSCs

The paracrine effect of NSCs has been shown to take significant therapeutic potential. Transplanting growth factor-secreting NSCs increased neurogenesis and cerebral function in a rodent Ad model [xvi] and anile primate brain [17], while transplantation of choline acetyltransferase-overexpressing human NSCs into a cholinergic neurotoxic rodent model resulted in a reversal of spatial memory and learning deficits [18]. Other contempo AD rodent model studies have reported that NSC transplantation decreased neuroinflammation [19], attenuation of tau and Aβ AD neuropathology [twenty], promotion of neurogenesis and synaptogenesis [21, 22], and reversal of cognitive deficits [xix, 21, 22]. While the therapeutic mechanisms behind these changes are not yet fully understood, they are likely mediated past both the paracrine release of neuroprotective or immune modulatory factors [16] and by direct neuronal differentiation [thirteen, 23], although the widespread generation of non-neuronal glial cell types from transplanted NSCs remains a major limiting factor for neuroreplacement strategies [23].

MSCs

Due to their accessibility, relative ease of treatment, and the broad range of cell types that they are able to generate, MSCs are now among the most frequently studied stem prison cell type. In aged rodent models, transplanted MSCs were shown to undergo differentiation into neural cell types, increasing local concentrations of acetylcholine neurotransmitter, BDNF, and NGF, and improving locomotor and cognitive role [24]. Even so, to date there has been picayune evidence for the functional or synaptic maturation of MSC-derived neurons in vivo. Moreover, 18-carat neuroreplacement by MSCs remains limited by low rates of neuronal differentiation and a propensity for glial cell formation in vivo [25]. Potentially of greater therapeutic significance are the reported neuroprotective paracrine effects of MSCs, with the introduction of MSC-secreted factors able to stimulate proliferation, neuronal differentiation, and survival in endogenous neurogenic niches [26, 27] and in cellular models of AD [28]. Similarly, in rodent AD models, MSC transplantation has been reported to inhibit Aβ- and tau-related cell death [28, 29], reduce Aβ deposits and plaque formation [xxx,31,32,33], stimulate neurogenesis, synaptogenesis, and neuronal differentiation [28, 31, 34], and rescue spatial learning and retention deficits [29,30,31,32]. Some studies suggest a further anti-inflammatory and immune modulatory paracrine effect for transplanted MSCs, including upregulated neuroprotective cytokines such every bit IL-ten, and reduced levels of pro-inflammatory cytokines TNF-α and IL-1β [29,30,31,32]. Intravenously administered MSCs are besides capable of crossing the blood-encephalon barrier and finer migrating to regions of neural injury, without inducing a tumourigenic or immune response [35]. This minimally invasive arroyo has pregnant advantages over traditional intracranial injection when considering man clinical translation, although reports of MSCs infiltrating into multiple organs remains a concern for this delivery system [34, 35].

iPSCs

iPSC-derived neurons are structurally and functionally mature, and capable of forming electrophysiologically active synaptic networks [36]. Using boosted transcription factors during the induction process, it has also been possible to straight differentiation into specific neuronal subtypes, such equally dopaminergic neurons [37]. Equally iPSCs are a relatively new technology, preclinical animal model transplantation studies are few. 1 written report in an ischaemic stroke rodent model demonstrated that man iPSC-derived NSCs were able to better neurological role and reduce pro-inflammatory factors through a neurotrophin-associated eyewitness effect [38]. In another recent study, post-obit intra-hippocampal transplantation into a transgenic Advert mouse model, man iPSC-derived cholinergic neuronal precursors survived, differentiated into phenotypically mature cholinergic neurons, and reversed spatial memory impairment [39].

iPSC applied science allows for the production of autologous pluripotent stalk cells, thereby fugitive both the ethical limitations and allowed rejection issues of non-patient-specific sources. Long-term survival and efficacy of autologous iPSC-derived dopaminergic neuronal transplantation has been demonstrated in a simian Parkinson'southward disease model, with improved motor activity and office, and extensive cell survival and engraftment at 2-years post-operation [twoscore]. However, autologous iPSCs may be of limited use for neuroreplacement equally neurons generated from Advertizing patients display phenotypic neuropathology, including abnormal Aβ levels, elevated tau phosphorylation, reduced neurite length, and altered electrocompetency [41,42,43]. Alternatively, using iPSC-derived neurons to recapitulate AD pathology in vitro has significant applications in the study of pathogenesis and screening for potential therapeutic drugs. As such, they are at present the subject of extensive study in vitro, every bit reviewed elsewhere [44].

Stalk cell trials in humans

Inconsistencies in preclinical studies have prevented several potential stem cell therapies from transitioning to man clinical trials. By dissimilarity, show for the rubber and efficacy of MSC-based therapies in brute models, combined with ease of handling and isolation, has supported the approval of several man clinical trials.

A recently completed open up-label phase I clinical trial evaluated the safety and the tolerability of intracranially injected allogeneic human umbilical cord blood-derived MSCs (Trial identifier: NCT01297218, NCT01696591) [45]. Ix patients, divers by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Affliction and Related Disorders Association criteria equally having probable Advertizing, were enrolled in the trial. Mini-Mental State Examination scoring between 10 and 24 (mild-moderate AD dementia), and Pittsburgh chemical compound B positron emission tomography confirmation of Aβ pathology were used as inclusion criteria. Trial participants were then divided into low-dose (3 × 10⁶ cells; n = three) and high-dose (6 × 10⁶ cells; n = 6) groups, and received bilateral stereotactic injection of human being umbilical cord blood-derived MSCs into the hippocampus and precuneus. At iii months and 24 months post-treatment time points, no patient showed any serious agin event resulting from either the surgical procedure or transplantation of MSCs. However, MSC transplantation did not ho-hum cognitive decline over the 24 months of follow-upwards, equally measured past the Alzheimer's Disease Cess Scale-cerebral subscale. Furthermore, no changes to Advertising pathology were observed. The neuroprotective effect of MSCs, frequently reported in AD animal models [thirty,31,32], was therefore not evident. The authors suggest this may exist due in office to a reliance on neuroimaging rather than more sensitive post-mortem biochemical analyses used in animal studies.

Details of ongoing trials are summarised in Table two. While many of these utilize an intravenous infusion administration route, ane trial (Trial identifier: NCT02054208) volition assess the prophylactic and efficacy of intraventricular MSC injection via an Ommaya reservoir arrangement. Umbilical string blood-derived MSCs remain a common prison cell pick, although fundamental differences be with regards to cell number, dose number, and dose schedule. Ii separate trials, both currently undergoing recruitment, will apply alternative MSC sources. I trial (Trial identifier: NCT02912169) will assess the rubber and efficacy of autologous adipose-derived stromal vascular fraction cells acquired from patient liposuction. Another report (Trial identifier: NCT02833792) will utilise ischaemia-tolerant allogeneic human os marrow-derived MSCs. Grown under hypoxic weather to more closely resemble the physiological environs of the CNS, these MSCs limited college levels of angiogenic growth factors, including VEGF and angiopoietin, and bear witness enhanced migratory activity [46].

Table 2 Ongoing stem cell trials in humans with Alzheimer'southward disease

Total size tabular array

Time to come directions

Preclinical studies suggest that stem cells take potential for the handling of Advertizing; however, this area is notable for poor translation between animal studies and human being trials. Indeed, researchers have finer treated Advert in transgenic mouse models in more than 50 different ways [47]. Transgenic models demonstrate little, if any, predictive utility. Their outcomes are oftentimes model-dependent and, disappointingly, each arroyo has failed in man clinical trials. Transgenic models are largely based on familial AD-related hypotheses in a genetically homogeneous population, while the vast majority of human Advertizement occurs sporadically amongst a distinctly heterogeneous population. Moreover, they do not restate the extensive neuronal and synaptic loss that is central to Advertisement. Clearly, rodent models and their aetiological hypotheses are inadequate for predicting human clinical outcomes. AD jail cell therapies will therefore need to demonstrate success in higher-order animals that more faithfully mimic the clinical and neurodegenerative features of the man status.

Several key questions likewise demand to be addressed, including long-term safety, optimum jail cell source and the delivery organisation, understanding donor cell response to the pathogenic AD environment, and clarifying the mechanisms of action. Many of the studies discussed hither utilised inherently heterotopic stem cells. While this is a clinically relevant strategy due to the inaccessible nature of the adult NSC niche, this too requires conscientious consideration. Human and rodent studies have reported tumour formation resulting from autologous haematopoietic stem cell [48], allogeneic fetal NSC [49], and genetically engineered MSC [l] transplantation. While neuroreplacement therapies may not be able to fully compensate for widespread and progressive neuronal loss, they may serve to temporarily heighten existing depleted circuits, which is sufficient to improve knowledge office, restore daily function, and better quality of life. Upon diagnosis, lifespan for individuals with Advertizing dementia is four–five years, and and then if a neuroreplacement therapy could rescue and protect brain function for that timespan information technology is commensurate to a functional cure. Alternatively, due to the complex nature of AD pathophysiology, a multimodal approach may be required, incorporating pharmacological targeting of pathology, stimulation of endogenous neurogenesis and synaptogenesis, as well as exogenous neuroreplacement.

Conclusion

Stem cell therapy for Ad carries enormous promise but remains under development. There is now noun preclinical literature that demonstrates proof-of-concept, with new studies continuing to reveal potential therapeutic mechanisms. MSC-based therapeutics take been the about consequent and have reached homo clinical trials. To date, 1 such trial was negative but there are many others underway. Researchers must, yet, be enlightened of the perilous gulf that lies between rodents and humans. Not but exercise nosotros demand to better sympathise the cells and the brains they intend to repair, but also employ translational models that begin to bridge this gap.

Abbreviations

Aβ:

Amyloid beta

AD:

Alzheimer'due south affliction

ApoE4:

Apolipoprotein-E4

BDNF:

Encephalon-derived neurotrophic gene

CA:

Cornu Ammonis

CNS:

Central nervous organisation

ESC:

Embryonic stem cell

GABA:

Gamma-aminobutyric acid

IGF-1:

Insulin growth cistron-one

IL:

Interleukin

iPSC:

Induced pluripotent stem jail cell

MSC:

Mesenchymal stem cell

NGF:

Nerve growth factor

NO:

Nitric oxide

NSC:

Neural stem cell

TNF:

Neoplasm necrosis factor

UCB-MSC:

Umbilical cord blood-derived mesenchymal stalk cell

VEGF:

Vascular endothelial growth factor

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Acknowledgements

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The human clinical trials data included in this review are available at https://clinicaltrials.gov/.

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TD and MV were involved in the writing, revision, and final approval of the manuscript.

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   Thomas Duncan & Michael Valenzuela

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Correspondence to Michael Valenzuela.

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Duncan, T., Valenzuela, M. Alzheimer's affliction, dementia, and stem cell therapy. Stem Cell Res Ther 8, 111 (2017). https://doi.org/10.1186/s13287-017-0567-5

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• Published: 12 May 2017

• DOI : https://doi.org/10.1186/s13287-017-0567-five

Keywords

• Alzheimer's disease
• Embryonic stem cells
• Induced pluripotent stem cells
• Mesenchymal stem cells
• Neural stem cells

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