Next Article in Journal
Experimental Treatments for Oedema in Spinal Cord Injury: A Systematic Review and Meta-Analysis
Next Article in Special Issue
Spontaneous Calcium Oscillations through Differentiation: A Calcium Imaging Analysis of Rat Cochlear Nucleus Neural Stem Cells
Previous Article in Journal
An Oil Hyper-Accumulator Mutant Highlights Peroxisomal ATP Import as a Regulatory Step for Fatty Acid Metabolism in Aurantiochytrium limacinum
Previous Article in Special Issue
Uncovering the Metabolic and Stress Responses of Human Embryonic Stem Cells to FTH1 Gene Silencing
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Stem Cell Research Tools in Human Metabolic Disorders: An Overview

1
Department of Cell Physiology and Metabolism, School of Medicine, University of Geneva, Rue Michel Servet 1, 1206 Geneva, Switzerland
2
Department of Pathology and Immunology, School of Medicine, University of Geneva, Rue Michel Servet 1, 1206 Geneva, Switzerland
*
Author to whom correspondence should be addressed.
Cells 2021, 10(10), 2681; https://doi.org/10.3390/cells10102681
Submission received: 1 September 2021 / Revised: 23 September 2021 / Accepted: 4 October 2021 / Published: 7 October 2021
(This article belongs to the Collection Researches on Normal and Cancer Stem Cells)

Abstract

:
Metabolic disorders are very common in the population worldwide and are among the diseases with the highest health utilization and costs per person. Despite the ongoing efforts to develop new treatments, currently, for many of these disorders, there are no approved therapies, resulting in a huge economic hit and tension for society. In this review, we recapitulate the recent advancements in stem cell (gene) therapy as potential tools for the long-term treatment of both inherited (lysosomal storage diseases) and acquired (diabetes mellitus, obesity) metabolic disorders, focusing on the main promising results observed in human patients and discussing the critical hurdles preventing the definitive jump of this approach from the bench to the clinic.

1. Introduction

Metabolic disorders usually occur as a result of loss and/or deficiency of enzymes or hormones indispensable for converting one metabolite to another metabolite [1]. Disorders of metabolism are very common in the population worldwide [2] and are among the diseases with the highest health utilization and costs per person [3]. Generally, these disorders are classified into two main groups: acquired and inherited [4]. Acquired metabolic diseases, such as diabetes mellitus or obesity, are linked to different external factors, such as an unhealthy lifestyle along with reduced physical exercise and high caloric intake [4]. Differently, inherited metabolic disorders, such as lysosomal storage diseases (LSDs), and peroxisomal and metal metabolism diseases, are caused by inborn errors of metabolism resulting from genetic defects [4]. While clinical trials are in progress for possible treatments for some of these diseases, there is currently no approved therapy for many of them, resulting in a huge economic hit and tension for society [5]. In this review, we recapitulate the recent advancements in stem cell and gene therapy as new potential tools in treating metabolic diseases, focusing on diabetes, obesity and LSDs, which account for the largest share of the global market of therapies for metabolic disorders. In particular, we highlight the main promising results observed in human patients, underlining the critical hurdles preventing the use of these methodologies in routine clinical practice.

1.1. Diabetes Mellitus

Diabetes mellitus (DM) represents one of the most critical and costly health issues affecting millions of people worldwide and contributing to 5% of global deaths in young people [6,7]. According to the most recent global report of the World Health Organization, the incidence of diabetes has strongly increased in recent years, especially in low and middle-income countries, with the number of people affected rising from 108 million in 1980 to 422 million in 2014, and an estimated 1.5 million deaths in 2012 directly caused by the disease (ISBN: 9789241565257, https://apps.who.int/iris/handle/10665/204871 accessed on 30 August 2021). Low-efficient pharmacological therapies together with poor patient compliance in the application of adequate life regimes strongly contribute to the increasing incidence of disease-related complications, which economically impacts countries’ health systems [8]. Thus, a major challenge in diabetes research is the identification of innovative therapeutic, or even curative, tools able to work at a group level to the extent of stopping the disease both at its early and late stages. In recent years, the stem cell strategy for curing DM has been arising great enthusiasm, as the approach offers the theoretical advantage of achieving a durable and definitive benefit by a single or a few treatments [9]. The pre-clinical data generated on animal models and the successful applications in human clinical trials deserve attention as potential curative tools for this disease (Figure 1).

1.2. Type 1 Diabetes (T1D)

T1D is a chronic disease of childhood and young adults that affects at least 30 million people worldwide, with an increasing incidence of 2–3% per year [10]. Despite the fact that in humans, many issues related to the immunological nature of T1D are still to be solved [11], it is widely accepted that the disease derives from an autoimmune destruction of insulin-producing β cells, resulting in insulin deficiency and hyperglycemia, necessitating lifelong insulin replacement [12]. Despite the fact that genome-wide association studies identified that approximately 50% of the genetic risk of the disease is attributable to human leukocyte antigens [13], the increasing incidence of T1D in recent decades has defined important implications of environmental/behavioral factors (e.g., infant diet, viruses, decreased gut microbiome diversity) [14]. Different animal models such as non-human primates [15,16], large animals (dog and pig) [17], rodents [18] and, recently, the non-mammalian zebrafish model (for its regenerative properties in different tissues [19]) [20,21] have been used to study the causes and complications of T1D. However, the exact causes of T1D are still poorly understood. The main symptoms ascribed to T1D are excessive hunger, excessive thirst, blurred vision, fatigue, frequent urination, weight loss in a short period of time and a dramatic complication of diabetes, known as ketoacidosis [22,23]. This complication includes rapid breathing, dry skin and mouth, flushed face, fruity breath odor, nausea, vomiting or stomach pain [24,25]. Tools for managing T1D continue to improve, although insulin remains the main therapy which, unfortunately, does not always achieve the correct metabolic control and cannot impede the occurrence of complications, requiring strict monitoring, education of patients and continuous insulin dose adjustments [26]. Furthermore, it has been shown that around 25.5% of patients with T1D can develop obesity and insulin resistance (“double diabetes”) [27]. This means the insulin they obtain from injections does not work as well as it should. For these patients, in addition to insulin therapy, the use of metformin, an oral medication commonly used in T2D management, has been approved, and it has been shown to reduce insulin dose requirements, although the appropriateness of its use is still controversial [28,29].

1.3. Current Advances in Stem Cell-Based Therapies for T1D

In recent years, big expectations have been placed on beta cell regeneration by the stem cell strategy as a promising cure for T1D [30]. The first enthusiastic results were obtained with the use of pluripotent stem cells (PSCs), including human embryonic stem cells (hESCs) and induced PSCs (iPSCs), which represent an unlimited supply of bona fide insulin-producing cells for autologous/allogenic transplantation [31]. Recent improvements in the PSC-derived beta cell microenvironment (e.g., microencapsulation) have allowed reducing the immune rejection of grafts and increasing the surface area for nutrients and oxygen to avoid ischemia [32]. However, the remaining challenges still need to be addressed regarding how to deliver PSC cells without great loss, without immune suppression and re-occurring autoimmunity and, in particular, with sufficient safety, in order to allow widespread implementation of PSC therapy for T1D patients [33]. Differently, the use of hematopoietic stem cells (HSCs) has recently been considered the most promising approach because of the differentiation and expansion capabilities of these cells, which ensure that a gene added to a small number of cells results in gene correction of much greater numbers of differentiated cells circulating in the whole organism [34,35,36]. Specifically, in curing type 1 diabetes, several studies in newly diagnosed T1D patients showed the powerful ability of autologous HSC transplantation to modulate T cell proliferation and pro-inflammatory cytokine production [37]. The immunomodulation reduces the aggressive autoimmune destruction of beta islets and has been observed to partially repristinate pancreas functionality and glycemic control [38]. However, the majority of patients who underwent transplantation were not able to achieve a long-lasting lowering of insulin dependence and prevention from its complications [39]. Finally, several studies have also explored the efficacy of the use of adult tissue-derived mesenchymal stem cells (MSCs) in T1D [40,41]. These studies reported the safety and efficacy of co-infusion of insulin-secreting adipose-derived MSCs and bone marrow-derived HSCs in patients with T1D, in which the use of an autologous inoculum appeared to confer better long-term control of hyperglycemia compared to allogenic stem cell transplantation [41]. The therapeutic property of MSCs has been revealed to be able to preserve the remaining existing beta cells, through immunomodulation, as well as giving rise to new functional ones [42]. Despite the vast number of sources of MSCs (bone marrow, adipose tissue, umbilical cord, etc.) and hypo-immunogenicity [43], data relative to their ability to differentiate into efficient beta cells remain controversial, and the doubt concerning spontaneous tumorigenicity capacities [44] still impedes the translation of this tool from the bench to beyond.

1.4. Type 2 Diabetes (T2D)

T2D represents the most common form of DM of great concern in global healthcare. In 2017, it was estimated that around 6.28% of the world’s population was affected by T2D, and, since then, over 1 million deaths per year have been attributed to this disease, making it the ninth leading cause of global mortality [45]. Multiple disturbances including impaired insulin secretion and insulin resistance in the main insulin-responding tissues (muscle, liver and adipocytes) contribute to the etiopathogenesis of T2D, resulting in abnormal glucose homeostasis [46]. Treatment of T2D remains mainly focused on ameliorating metabolic controls and on reducing the risk of acute and chronic complications (e.g., blindness, nerve damage, heart attack, stroke) [47]. In combination with improvements in patients’ lifestyle (physical activity, diet, etc.), the main therapeutic approach for patients with T2D is represented by metformin administration [48]. Metformin is able to reduce the hepatic glucose output, to enhance peripheral tissue insulin sensitivity and to stimulate GLP-1 secretion [49]. However, many other adjunctive/combined drugs have shown valuable efficacy in the management of the disease such as sulfonylureas, GLP-1 receptor agonists, SGLT-2 inhibitors and, recently, thiazolidinediones [47].

1.5. Stem Cell Therapy Approach to T2D

Stem cells have also been considered a highly promising means for the treatment of T2D due to the fact that, as in T1D, patients affected show an injured pancreas and impaired insulin production, especially in the late stage of the disease [50]. Stem cell administration indeed showed important immunomodulatory properties and a regenerative ability to stimulate the recovery of injured pancreases [51]. Different studies reported the generation of interspecific pancreatic chimeras from pancreatic stem cells [52] and the rat pancreas in mice [53], pigs [54] and rhesus monkeys [55]. While few pre-clinical reports have outlined the effectiveness of the use of iPSCs in T2D animal models [56,57], the majority of human studies, which found an encouraging applicability of this tool in the clinic, focused on the autologous administration of MSCs [58]. Pre-clinical data elucidated, indeed, that MSCs are not only able to differentiate in functional insulin-producing cells but are capable of preserving the integrity of the remaining beta cells and, overall, of promoting insulin sensitivity in peripheral tissue, activating insulin receptors and acting on macrophages’ inflammatory status [58]. In humans, transplantation of bone marrow-derived MSCs was observed to be safe and to have good tolerability, with a successful ability to not only improve metabolic parameters (e.g., glycemia, HbAc1, body weight, fat mass) but also to ameliorate disease-related complications [59,60]. Interestingly, patients who underwent treatment showed a lowering in insulin requirements, sustained in the long term, with improvements in insulin sensitivity [61,62]. Nevertheless, the great heterogenicity in the single patient clinical picture does not allow drawing a defined phase of the disease that the tools can be applicable in [63]. Moreover, the route of administration (targeted or peripheral) can have an important impact on the outcome, and thus it represents a limiting factor [64]. Finally, in spite of the tested safety, patients should remain under close surveillance for checking the eventual tumorigenicity potential of delivered cells [64].

1.6. Obesity

With more than 650 million people affected worldwide, obesity represents one of the most devastating health issues of Western industrialized countries [65]. The latest WHO report observed an increasing prevalence of this disorder that nearly tripled between 1975 and 2016, with a dramatic growing incidence in the pediatric age—more than 30 million children up to the age of 5 years old are obese (https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight accessed on 30 August 2021). The disease, broadly defined as an excess of body fat mass (body mass index (BMI) more than 30 kg/m2), has a complex etiology with a combination of genetic, hormonal and environmental factors [66]. Following the most recent recommendations for the non-pharmacological management of obesity, the main therapeutic approach for affected patients is diet therapy, physical activity and behavioral therapy [67]. However, for a great percentage of patients, initial success in weight loss can hardly be maintained in the longer term without constant vigilance to sustain behavior changes in the face of environmental pressures to regain weight [68]. This is why adjunctive drug therapies (statins, anorectics, anti-depressives, GLP-1 agonists, etc.) are required to help patients in sustaining sufficient weight loss and prevent obesity-associated complications (diabetes, vascular disease, hypertension, fatty liver, etc.) [69].

1.7. Stem Cell Therapy to Repristinate Metabolic Homeostasis in Obese Patients

The possibility to apply stem cell therapy in the treatment of obesity arose after a pre-clinical study observed that transplantation of adipose tissue from wild-type mice into ob/ob mice was able to repristinate metabolic homeostasis [70,71]. Some years later, these results found explanation in the phenomenon of adipose dysfunction characterizing obesity [72]. Patients with obesity show, indeed, an impaired adipose tissue function with adipocyte hypertrophy, hypoxia and inflammation which alter the cellular composition, increase lipid storage and impair insulin sensitivity [73]. The first attempts of stem cell therapy were, thus, intended to improve fat dysfunction by autologous transplantation of adipose-specific mesenchymal stem cells (called adipose-derived stem cells—ASCs), a population of multipotent cells with the ability to differentiate into various cell lineages [74]. Infusion of ASCs in high-fat diet-mediated obese mice showed a great improvement in body weight, glucose tolerance and dyslipidemia with a valuable reduction in fat tissue hyperplasia [75,76,77]. Despite the fact that no clinical study applying ASCs to treat obese patients has been started yet, the enthusiastic pre-clinical data obtained encourage the translation of this approach in humans, also considering the great availability of ASC sources [78]. In obese subjects, it has been shown, indeed, that minimally invasive and low-morbidity liposuction of subcutaneous/visceral fat allows isolation of an incredible amount of ASCs, sufficient for autologous transplantation [78]. Another interesting aspect related to stem cell application in the treatment of obesity is the potential of ex vivo differentiation into brown adipocytes, which is reported to improve obesity in animals and humans [79,80,81,82]. In this case, interesting results were obtained by the use of induced pluripotent stem cells (iPSCs) which can be easily collected and engineered ex vivo for being retransplanted into the original donor [83]. Transplantation of induced brown adipocytes (iBAs)—differentiated from epidermal-derived iPSCs—showed a strong ability to ameliorate the obese phenotype, by reducing body weight and ameliorating glucose tolerance and dyslipidemia [84]. In spite of these promising observations, transplantation in humans of ex vivo iBAs still seems to be a far-off goal, due to the difficulties in mimicking the fat physiological microenvironment. It has been observed, indeed, that highly vascularized lobular structures within adipose tissue correspond to the key environment where the browning phenomenon occurs and which cannot be re-produced in vitro [84,85].
Finally, a real challenging attempt to adopt stem cells to treat obesity has been conducted with the use of neural stem cells (NSCs). The role of the central nervous system in controlling appetite and feeding behavior [86,87] is widely recognized, and particularly very well described is the dense network between hypothalamic and non-hypothalamic hormones—but which acts at the hypothalamus levels—having a determined impact in the pathophysiology of obesity [87]. Recent evidence outlined that impaired food intake observed in obesity can be due to the inflammation-mediated loss of neural stem cells in the hypothalamus which affects the regeneration of neurons in this particular brain area [88,89]. In mice, it was shown that virus-mediated disruption of hypothalamic NSCs is able to induce glucose intolerance and to affect body weight [90], as well as knocking out the leptin receptor from these cells, which promotes an extreme obese phenotype [91]. However, realizing a concrete attempt to translate these studies in patients requires overcoming the strong controversy persisting in the scientific community about the existence of NSCs in the human brain [92,93].

1.8. Lysosomal Storage Diseases (LSDs)

Lysosomal storage diseases (LSDs) encompass more than 70 inherited diseases, which occur during infancy and childhood (1:5000 newborns), mainly characterized by a progressive neurodegenerative clinical course [94]. Despite the fact that the pathogenesis is still not currently well understood, the main mechanism causing the disease is the accumulation of metabolic substrates within lysosomes or peroxisomes, due to genetic defects in lysosomal enzymes or lysosomal membrane proteins [95,96,97]. Lysosomal dysfunction affects, basically, all body tissues, although its serious effects mainly concern the central nervous system, meaning that affected patients display progressive psycho-neurological impairments, accompanied by a broad spectrum of other clinical phenotypes, such as seizures, facial and other bone deformities, problems with vision and hearing, difficulty breathing, anemia and an enlarged spleen or liver [98,99]. For many LSDs, there are approved disease-specific therapies based on enzyme replacement (ERT) [100,101,102], or on intravenous administration of recombinant proteins [103,104,105], accompanied by treatment of the neurological complications, such as anticonvulsant medication, ventilatory support, assistance for patients with learning disability, orthopedic interventions and nutritional support [106,107]. Despite the good tolerability demonstrated by ERT, unfortunately, many symptoms, even after long-term treatment, are not reversible [108]. In addition, many patients showed development of antibodies against the exogenous enzyme/protein with a negative impact on the therapy efficacy [109]. This is particularly true for LSDs severely affecting the CNS [110,111,112]. New therapeutic drugs for several LSDs, including substrate inhibitors and chaperones, have been approved considering their ability to overcome ERT’s limitations; still, their efficacy seems to be variable among patients [113,114].

1.9. Treating LSDs by Stem Cell Gene Therapy

The approach of using stem cells for treating LSDs soon appeared as very challenging, but the promising advanced pre-clinical results have allowed many of these attempts to progress into clinical experimentation [115]. In particular, the use of stem cells has been referred to as a means for gene defect correction [115].
Several studies in animal models of different types of LSDs indeed showed that genetic editing of autologous/allogenic blood stem progenitors (HSCs) and their transplantation can ensure increased production of the missing lysosomal enzyme or protein [116,117,118,119], with partial improvements in the phenotypical features of the disease [120,121,122]. The rationale to apply HSC transplantation in LSDs lies in the ability of the transplanted cells and/or their progeny to contribute to fixed tissue macrophage populations in the affected tissues and to become local permanent sources of functional lysosomal enzymes [123,124,125] (Figure 2). Of note, interesting is the recent pre-clinical evidence in the stem cell approach to Pompe disease, where transplantation in mice of bone marrow-derived HSCs transduced by a highly efficient gene transfer method (a third-generation SIN-lentiviral vector containing a codon-optimized transgene driven by the strong SFFV promoter) resulted in high and sustained enzyme activity in the tissues that are most affected in Pompe disease [126].
In humans, the first trials, around 25 years ago, showed that in patients with Gaucher disease (lacking the functional glucocerebrosidase enzyme in macrophage cells), the autologous transplantation of viral-mediated modified HSCs (peripheral blood or bone marrow-derived) encoding the normal enzyme allows the amelioration of enzyme deficiency [127,128]. Some years later, a similar approach was tested in an animal model and three patients with neuronal ceroid lipofuscinosis (NCL) (lacking the functional palmitoyl protein thioesterase 1—PPT1) by transplanting them with genetically engineered bone marrow-derived HSCs overexpressing PPT1 [129]. However, PPT1 enzyme activity was normalized only in peripheral leukocytes with a mild amelioration of the clinic manifestations [130]. Functional improvements in cognitive and orthopedic features were observed to be long-lasting in patients affected by Hurler syndrome (deficient in lysosomal alpha-L-iduronidase activity) and transplanted with engineered peripheral blood-derived HSCs [131]. In addition, poor achievements with the first HSC transplantation can sometimes be improved by a second transplantation, which has shown good tolerance and clinical efficacy [132]. The approach of using modified peripheral blood-derived HSCs in pediatric patients affected by Faber disease (N-acylsphingosine amidohydrolase deficiency) provided an enthusiastic resolution of clinical manifestations, and patients survived for decades with no more complications [133,134]. Instead, peripheral blood-derived HSC delivery therapy in 17 patients affected by alpha-mannosidosis seemed to be less successful, as patients made scant developmental progress [135]. Still, amazing results were obtained from autologous infusion of gene-corrected peripheral blood-derived HSCs in patients affected by metachromatic leukodystrophy, for whom the disease stopped progressing in the long term [136,137].
Some challenging attempts at stem cell therapy application have also been conducted by the use of neuronal stem cell progenitors (NSCPs). Allogenic transplantation of NSCPs from healthy donors in newborn mice affected by mucopolysaccharidosis VII showed restoration of normal neural cell function [138,139]. Similarly, transplantation of NPCs genetically modified to overexpress the human beta-hexosaminidase alpha-subunit gene in mouse models of Tay-Sachs disease resulted in amelioration of neurological features with potential therapeutical insights [140]. Still, transplantation of genetically modified NPCs in mouse models of Niemann–Pick disease (deficiency in acid sphingomyelinase—ASM) seems to be sufficient to reverse lysosomal storage pathology [141]. Impressing results were also obtained by NPC transplantation in mouse models of NCL for repristinating PPT1 expression and neuroprotection [142].
Transplantation of genetically modified stem cells directly into the brain was also tested by the use of embryonic stem cells (ESCs). In guinea pig models of alpha-mannosidosis (alpha-d-mannosidase enzyme deficiency), modified ESCs were successfully implanted [143]; however, uncontrolled cell proliferation and formation of brain teratomas drew the unfeasibility in the use of this pluripotent cell type for achieving longer-term disease treatment [143]. On the contrary, some years later, in a mouse model of Sanfilippo syndrome (mucopolysaccharidosis IIIA), intracerebral transplantation of sulfamidase-expressing ESCs was observed to be safe [144].
Further studies, in recent years, have also shown the possibility to easily obtain autologous stem cells by non-invasive methods, and in a greater volume, by the use of induced pluripotent stem cells (iPSCs) [145]. Pre-clinical evidence in animal models of LSDs showed that brain administration of corrected iPSC-derived neuronal stem precursors was able to reverse the neuropathology in a zone surrounding the grafts [146,147]; however, their application in humans still seems to be far away [148]. In Supplemental Table S1, we report all recent stem cell (gene) therapy applications in animal models and/or human patients for different metabolic disorders.

2. Conclusions and Perspectives

In conclusion, despite the fact that greater efforts are still needed for solving the remaining issues hampering the translation of the stem cell approach into the clinical routine for the management of type 1 and type 2 diabetes patients, the promising achievements obtained until now give us hope and solid expectations that a disease, until now considered “uncurable”, could be definitively cured in the near future. Despite this, envisioning the application of cell therapy in such a multifactorial disease as obesity remains challenging; however, history has taught that scientific potential and improvements in technology can turn a far-off goal into a powerful reality. Differently, it is possible to assess that stem cell-based therapy in the management of LSDs has been revealed as the most promising and effective tool in the long term for curing these diseases. In perspective, further studies are surely needed in order to define standardized protocols for clinical application of stem cells in metabolic disorders. However, the research efforts until now and those ongoing encourage the medico-scientific community in tackling the great step head which can be conducted with these new therapies to significantly improve patients’ life quality and prolong their survival.

Supplementary Materials

The following are available online at https://www.mdpi.com/article/10.3390/cells10102681/s1, Table S1: Landmark reports of stem cell (gene) therapy application in animal models and/or human patients for the different metabolic disorders.

Author Contributions

Conceptualization, S.R. and P.C.; writing, S.R.; review and editing, S.R. and P.C.; figures, P.C. by using Biorender® software. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the reviewer activity of P.C. He is also supported by the Gertrude von Meissner Foundation 2020 and Ernest Boninchi Foundation 2021.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Chaturvedi, S.; Singh, A.K.; Keshari, A.K.; Maity, S.; Sarkar, S.; Saha, S. Human Metabolic Enzymes Deficiency: A Genetic Mutation Based Approach. Scientifica 2016, 2016, 9828672. [Google Scholar] [CrossRef] [Green Version]
  2. Aguilar, M.; Bhuket, T.; Torres, S.; Liu, B.; Wong, R.J. Prevalence of the Metabolic Syndrome in the United States, 2003–2012. JAMA J. Am. Med. Assoc. 2015, 313, 1973–1974. [Google Scholar] [CrossRef] [PubMed]
  3. Boudreau, D.M.; Malone, D.C.; Raebel, M.A.; Fishman, P.A.; Nichols, G.A.; Feldstein, A.C.; Boscoe, A.N.; Ben-Joseph, R.H.; Magid, D.J.; Okamoto, L.J. Health Care Utilization and Costs by Metabolic Syndrome Risk Factors. Metab. Syndr. Relat. D 2009, 7, 305–313. [Google Scholar] [CrossRef] [PubMed]
  4. Eichler, F.; Ratai, E.; Carroll, J.J.; Masdeu, J.C. Inherited or acquired metabolic disorders. Handb. Clin. Neurol. 2016, 135, 603–636. [Google Scholar] [PubMed]
  5. Saklayen, M.G. The Global Epidemic of the Metabolic Syndrome. Curr. Hypertens. Rep. 2018, 20, 12. [Google Scholar] [CrossRef] [Green Version]
  6. Khan, M.A.B.; Hashim, M.J.; King, J.K.; Govender, R.D.; Mustafa, H.; Al Kaabi, J. Epidemiology of Type 2 Diabetes—Global Burden of Disease and Forecasted Trends. J. Epidemiol. Glob. Health 2020, 10, 107–111. [Google Scholar] [CrossRef] [Green Version]
  7. Liu, J.; Ren, Z.H.; Qiang, H.; Wu, J.; Shen, M.; Zhang, L.; Lyu, J. Trends in the incidence of diabetes mellitus: Results from the Global Burden of Disease Study 2017 and implications for diabetes mellitus prevention. BMC Public Health 2020, 20, 1415. [Google Scholar] [CrossRef]
  8. Ahern, D.K.; Aberger, E.W.; Wroblewski, J.P.; Zheng, Q.; Mehta, S.N.; Buchanan, A.L.; Shah, K.K.; Rocchio, R.J.; Follick, M.J. Behavior-based diabetes management: Impact on care, hospitalizations, and costs. Am. J. Manag. Care 2021, 27, 96–102. [Google Scholar]
  9. Sneddon, J.B.; Tang, Q.; Stock, P.; Bluestone, J.A.; Roy, S.; Desai, T.; Hebrok, M. Stem Cell Therapies for Treating Diabetes: Progress and Remaining Challenges. Cell Stem Cell 2018, 22, 810–823. [Google Scholar] [CrossRef] [Green Version]
  10. DiMeglio, L.A.; Evans-Molina, C.; Oram, R.A. Type 1 diabetes. Lancet 2018, 391, 2449–2462. [Google Scholar] [CrossRef]
  11. Notkins, A.L.; Lernmark, A. Autoimmune type 1 diabetes: Resolved and unresolved issues. J. Clin. Investig. 2001, 108, 1247–1252. [Google Scholar] [CrossRef] [PubMed]
  12. Evans-Molina, C.; Sims, E.K.; DiMeglio, L.A.; Ismail, H.M.; Steck, A.K.; Palmer, J.P.; Krischer, J.P.; Geyer, S.; Xu, P.; Sosenko, J.M.; et al. Beta Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis. JCI Insight 2018, 3, e120877. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Warshauer, J.T.; Bluestone, J.A.; Anderson, M.S. New Frontiers in the Treatment of Type 1 Diabetes. Cell Metab. 2020, 31, 46–61. [Google Scholar] [CrossRef]
  14. Rewers, M.; Ludvigsson, J. Environmental risk factors for type 1 diabetes. Lancet 2016, 387, 2340–2348. [Google Scholar] [CrossRef] [Green Version]
  15. Batista, A.F.; Forny-Germano, L.; Clarke, J.R.; Lyra, E.S.N.M.; Brito-Moreira, J.; Boehnke, S.E.; Winterborn, A.; Coe, B.C.; Lablans, A.; Vital, J.F.; et al. The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer’s disease. J. Pathol. 2018, 245, 85–100. [Google Scholar] [CrossRef]
  16. Thomson, S.E.; McLennan, S.V.; Kirwan, P.D.; Heffernan, S.J.; Hennessy, A.; Yue, D.K.; Twigg, S.M. Renal connective tissue growth factor correlates with glomerular basement membrane thickness and prospective albuminuria in a non-human primate model of diabetes: Possible predictive marker for incipient diabetic nephropathy. J. Diabetes Complicat. 2008, 22, 284–294. [Google Scholar] [CrossRef] [PubMed]
  17. Pepper, A.R.; Welch, I.; Bruni, A.; MacGillivary, A.; Mazzuca, D.M.; White, D.J.; Wall, W. Establishment of a stringent large animal model of insulin-dependent diabetes for islet autotransplantation: Combination of pancreatectomy and streptozotocin. Pancreas 2013, 42, 329–338. [Google Scholar] [CrossRef]
  18. Wu, J.; Yan, L.J. Streptozotocin-induced type 1 diabetes in rodents as a model for studying mitochondrial mechanisms of diabetic beta cell glucotoxicity. Diabetes Metab. Syndr. Obes. 2015, 8, 181–188. [Google Scholar] [PubMed] [Green Version]
  19. Lucini, C.; D’Angelo, L.; Cacialli, P.; Palladino, A.; de Girolamo, P. BDNF, Brain, and Regeneration: Insights from Zebrafish. Int. J. Mol. Sci. 2018, 19, 3155. [Google Scholar] [CrossRef] [Green Version]
  20. Salehpour, A.; Rezaei, M.; Khoradmehr, A.; Tahamtani, Y.; Tamadon, A. Which Hyperglycemic Model of Zebrafish (Danio rerio) Suites My Type 2 Diabetes Mellitus Research? A Scoring System for Available Methods. Front. Cell Dev. Biol. 2021, 9, 652061. [Google Scholar] [CrossRef]
  21. Cacialli, P. Neurotrophins Time Point Intervention after Traumatic Brain Injury: From Zebrafish to Human. Int. J. Mol. Sci. 2021, 22, 1585. [Google Scholar]
  22. Van Name, M.A.; Hilliard, M.E.; Boyle, C.T.; Miller, K.M.; DeSalvo, D.J.; Anderson, B.J.; Laffel, L.M.; Woerner, S.E.; DiMeglio, L.A.; Tamborlane, W.V. Nighttime is the worst time: Parental fear of hypoglycemia in young children with type 1 diabetes. Pediatr. Diabetes 2018, 19, 114–120. [Google Scholar] [CrossRef]
  23. Sims, E.K.; Bahnson, H.T.; Nyalwidhe, J.; Haataja, L.; Davis, A.K.; Speake, C.; DiMeglio, L.A.; Blum, J.; Morris, M.A.; Mirmira, R.G.; et al. Proinsulin Secretion Is a Persistent Feature of Type 1 Diabetes. Diabetes Care 2019, 42, 258–264. [Google Scholar] [CrossRef] [Green Version]
  24. Takagi, Y. Chemical analysis of diseases. 4. Etiology and major symptoms of diabetes mellitus. Kango Kyoshitsu 1973, 17, 48–49. [Google Scholar] [PubMed]
  25. Abid, S.; Rizvi, A.; Jahan, F.; Rabbani, F.; Islam, N.; Khan, M.H.; Masood, R.; Jafri, W. Poor glycaemic control is the major factor associated with increased frequency of gastrointestinal symptoms in patients with diabetes mellitus. J. Pak. Med. Assoc. 2007, 57, 345–349. [Google Scholar] [PubMed]
  26. Dong, S.; Lau, H.; Chavarria, C.; Alexander, M.; Cimler, A.; Elliott, J.P.; Escovar, S.; Lewin, J.; Novak, J.; Lakey, J.R.T. Effects of Periodic Intensive Insulin Therapy: An Updated Review. Curr. Ther. Res. Clin. Exp. 2019, 90, 61–67. [Google Scholar] [CrossRef] [PubMed]
  27. Khawandanah, J. Double or hybrid diabetes: A systematic review on disease prevalence, characteristics and risk factors. Nutr. Diabetes 2019, 9, 33. [Google Scholar] [CrossRef] [PubMed]
  28. Beysel, S.; Unsal, I.O.; Kizilgul, M.; Caliskan, M.; Ucan, B.; Cakal, E. The effects of metformin in type 1 diabetes mellitus. BMC Endocr. Disord. 2018, 18, 1. [Google Scholar] [CrossRef] [Green Version]
  29. Faichney, J.D.; Tate, P.W. Metformin in type 1 diabetes: Is this a good or bad idea? Diabetes Care 2003, 26, 1655. [Google Scholar] [CrossRef] [Green Version]
  30. Aguayo-Mazzucato, C.; Bonner-Weir, S. Stem cell therapy for type 1 diabetes mellitus. Nat. Rev. Endocrinol. 2010, 6, 139–148. [Google Scholar] [CrossRef]
  31. Kimbrel, E.A.; Lanza, R. Pluripotent stem cells: The last 10 years. Regen Med. 2016, 11, 831–847. [Google Scholar] [CrossRef] [Green Version]
  32. Kimbrel, E.A.; Lanza, R. Current status of pluripotent stem cells: Moving the first therapies to the clinic. Nat. Rev. Drug Discov. 2015, 14, 681–692. [Google Scholar] [CrossRef] [PubMed]
  33. Dadheech, N.; James Shapiro, A.M. Human Induced Pluripotent Stem Cells in the Curative Treatment of Diabetes and Potential Impediments Ahead. Adv. Exp. Med. Biol. 2019, 1144, 25–35. [Google Scholar] [PubMed]
  34. Morgan, R.A.; Gray, D.; Lomova, A.; Kohn, D.B. Hematopoietic Stem Cell Gene Therapy: Progress and Lessons Learned. Cell Stem Cell 2017, 21, 574–590. [Google Scholar] [CrossRef] [Green Version]
  35. Cacialli, P.; Mahony, C.B.; Petzold, T.; Bordignon, P.; Rougemont, A.L.; Bertrand, J.Y. A connexin/ifi30 pathway bridges HSCs with their niche to dampen oxidative stress. Nat. Commun. 2021, 12, 4484. [Google Scholar] [CrossRef] [PubMed]
  36. Mahony, C.B.; Cacialli, P.; Pasche, C.; Monteiro, R.; Savvides, S.N.; Bertrand, J.Y. Hapln1b, a central organizer of the extracellular matrix, modulates kit signalling to control developmental haematopoiesis. Blood Adv. 2021. [Google Scholar] [CrossRef] [PubMed]
  37. Ye, L.; Li, L.; Wan, B.; Yang, M.; Hong, J.; Gu, W.; Wang, W.; Ning, G. Immune response after autologous hematopoietic stem cell transplantation in type 1 diabetes mellitus. Stem Cell Res. Ther. 2017, 8, 90. [Google Scholar] [CrossRef] [Green Version]
  38. Voltarelli, J.C.; Couri, C.E.; Stracieri, A.B.; Oliveira, M.C.; Moraes, D.A.; Pieroni, F.; Coutinho, M.; Malmegrim, K.C.; Foss-Freitas, M.C.; Simoes, B.P.; et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA 2007, 297, 1568–1576. [Google Scholar] [CrossRef] [Green Version]
  39. D’Addio, F.; Valderrama Vasquez, A.; Ben Nasr, M.; Franek, E.; Zhu, D.; Li, L.; Ning, G.; Snarski, E.; Fiorina, P. Autologous nonmyeloablative hematopoietic stem cell transplantation in new-onset type 1 diabetes: A multicenter analysis. Diabetes 2014, 63, 3041–3046. [Google Scholar] [CrossRef] [Green Version]
  40. Cai, J.; Wu, Z.; Xu, X.; Liao, L.; Chen, J.; Huang, L.; Wu, W.; Luo, F.; Wu, C.; Pugliese, A.; et al. Umbilical Cord Mesenchymal Stromal Cell with Autologous Bone Marrow Cell Transplantation in Established Type 1 Diabetes: A Pilot Randomized Controlled Open-Label Clinical Study to Assess Safety and Impact on Insulin Secretion. Diabetes Care 2016, 39, 149–157. [Google Scholar] [CrossRef] [Green Version]
  41. Ulyanova, O.; Askarov, M.; Kozina, L.; Karibekov, T.; Shaimardanova, G.; Zhakupova, A.; Danilova, D.; Serebrennikova, D. Autologous Mesenchymal Stem Cell Transplant in Patients with Type 1 Diabetes Mellitus. Exp. Clin. Transplant. 2019, 17 (Suppl. S1), 236–238. [Google Scholar] [CrossRef]
  42. Carlsson, P.O.; Schwarcz, E.; Korsgren, O.; Le Blanc, K. Preserved beta-cell function in type 1 diabetes by mesenchymal stromal cells. Diabetes 2015, 64, 587–592. [Google Scholar] [CrossRef] [Green Version]
  43. Vija, L.; Farge, D.; Gautier, J.F.; Vexiau, P.; Dumitrache, C.; Bourgarit, A.; Verrecchia, F.; Larghero, J. Mesenchymal stem cells: Stem cell therapy perspectives for type 1 diabetes. Diabetes Metab. 2009, 35, 85–93. [Google Scholar] [CrossRef] [PubMed]
  44. Neri, S. Genetic Stability of Mesenchymal Stromal Cells for Regenerative Medicine Applications: A Fundamental Biosafety Aspect. Int. J. Mol. Sci. 2019, 20, 2406. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Zheng, Y.; Ley, S.H.; Hu, F.B. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat. Rev. Endocrinol. 2018, 14, 88–98. [Google Scholar] [CrossRef]
  46. Chatterjee, S.; Khunti, K.; Davies, M.J. Type 2 diabetes. Lancet 2017, 389, 2239–2251. [Google Scholar] [CrossRef]
  47. Stumvoll, M.; Goldstein, B.J.; van Haeften, T.W. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet 2005, 365, 1333–1346. [Google Scholar] [CrossRef]
  48. Sanchez-Rangel, E.; Inzucchi, S.E. Metformin: Clinical use in type 2 diabetes. Diabetologia 2017, 60, 1586–1593. [Google Scholar] [CrossRef]
  49. Foretz, M.; Guigas, B.; Bertrand, L.; Pollak, M.; Viollet, B. Metformin: From mechanisms of action to therapies. Cell Metab. 2014, 20, 953–966. [Google Scholar] [CrossRef] [Green Version]
  50. Walker, A.E. The Adult Pancreas in Trauma and Disease. Acad. Forensic Pathol. 2018, 8, 192–218. [Google Scholar] [CrossRef]
  51. Zhang, Y.; Chen, W.; Feng, B.; Cao, H. The Clinical Efficacy and Safety of Stem Cell Therapy for Diabetes Mellitus: A Systematic Review and Meta-Analysis. Aging Dis. 2020, 11, 141–153. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Yamaguchi, T.; Sato, H.; Kato-Itoh, M.; Goto, T.; Hara, H.; Sanbo, M.; Mizuno, N.; Kobayashi, T.; Yanagida, A.; Umino, A.; et al. Interspecies organogenesis generates autologous functional islets. Nature 2017, 542, 191–196. [Google Scholar] [CrossRef] [PubMed]
  53. Kobayashi, T.; Yamaguchi, T.; Hamanaka, S.; Kato-Itoh, M.; Yamazaki, Y.; Ibata, M.; Sato, H.; Lee, Y.S.; Usui, J.; Knisely, A.S.; et al. Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell 2010, 142, 787–799. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Matsunari, H.; Nagashima, H.; Watanabe, M.; Umeyama, K.; Nakano, K.; Nagaya, M.; Kobayashi, T.; Yamaguchi, T.; Sumazaki, R.; Herzenberg, L.A.; et al. Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proc. Natl. Acad. Sci. USA 2013, 110, 4557–4562. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Tachibana, M.; Sparman, M.; Ramsey, C.; Ma, H.; Lee, H.S.; Penedo, M.C.; Mitalipov, S. Generation of chimeric rhesus monkeys. Cell 2012, 148, 285–295. [Google Scholar] [CrossRef] [Green Version]
  56. Gheibi, S.; Singh, T.; da Cunha, J.; Fex, M.; Mulder, H. Insulin/Glucose-Responsive Cells Derived from Induced Pluripotent Stem Cells: Disease Modeling and Treatment of Diabetes. Cells 2020, 9, 2465. [Google Scholar] [CrossRef]
  57. Alipio, Z.; Liao, W.; Roemer, E.J.; Waner, M.; Fink, L.M.; Ward, D.C.; Ma, Y. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc. Natl. Acad. Sci. USA 2010, 107, 13426–13431. [Google Scholar] [CrossRef] [Green Version]
  58. Zang, L.; Hao, H.; Liu, J.; Li, Y.; Han, W.; Mu, Y. Mesenchymal stem cell therapy in type 2 diabetes mellitus. Diabetol. Metab. Syndr. 2017, 9, 36. [Google Scholar] [CrossRef] [Green Version]
  59. Al Demour, S.; Jafar, H.; Adwan, S.; AlSharif, A.; Alhawari, H.; Alrabadi, A.; Zayed, A.; Jaradat, A.; Awidi, A. Safety and Potential Therapeutic Effect of Two Intracavernous Autologous Bone Marrow Derived Mesenchymal Stem Cells injections in Diabetic Patients with Erectile Dysfunction: An Open Label Phase I Clinical Trial. Urol. Int. 2018, 101, 358–365. [Google Scholar] [CrossRef]
  60. Chen, Y.; Ma, Y.; Li, N.; Wang, H.; Chen, B.; Liang, Z.; Ren, R.; Lu, D.; Boey, J.; Armstrong, D.G.; et al. Efficacy and long-term longitudinal follow-up of bone marrow mesenchymal cell transplantation therapy in a diabetic patient with recurrent lower limb bullosis diabeticorum. Stem Cell Res. Ther. 2018, 9, 99. [Google Scholar] [CrossRef]
  61. Bhansali, S.; Dutta, P.; Kumar, V.; Yadav, M.K.; Jain, A.; Mudaliar, S.; Bhansali, S.; Sharma, R.R.; Jha, V.; Marwaha, N.; et al. Efficacy of Autologous Bone Marrow-Derived Mesenchymal Stem Cell and Mononuclear Cell Transplantation in Type 2 Diabetes Mellitus: A Randomized, Placebo-Controlled Comparative Study. Stem Cells Dev. 2017, 26, 471–481. [Google Scholar] [CrossRef] [PubMed]
  62. Bhansali, A.; Asokumar, P.; Walia, R.; Bhansali, S.; Gupta, V.; Jain, A.; Sachdeva, N.; Sharma, R.R.; Marwaha, N.; Khandelwal, N. Efficacy and safety of autologous bone marrow-derived stem cell transplantation in patients with type 2 diabetes mellitus: A randomized placebo-controlled study. Cell Transplant. 2014, 23, 1075–1085. [Google Scholar] [CrossRef]
  63. Qi, Y.; Ma, J.; Li, S.; Liu, W. Applicability of adipose-derived mesenchymal stem cells in treatment of patients with type 2 diabetes. Stem Cell Res. Ther. 2019, 10, 274. [Google Scholar] [CrossRef]
  64. Mishra, V.K.; Shih, H.H.; Parveen, F.; Lenzen, D.; Ito, E.; Chan, T.F.; Ke, L.Y. Identifying the Therapeutic Significance of Mesenchymal Stem Cells. Cells 2020, 9, 1145. [Google Scholar] [CrossRef]
  65. Bluher, M. Obesity: Global epidemiology and pathogenesis. Nat. Rev. Endocrinol. 2019, 15, 288–298. [Google Scholar] [CrossRef]
  66. Oussaada, S.M.; van Galen, K.A.; Cooiman, M.I.; Kleinendorst, L.; Hazebroek, E.J.; van Haelst, M.M.; Ter Horst, K.W.; Serlie, M.J. The pathogenesis of obesity. Metabolism 2019, 92, 26–36. [Google Scholar] [CrossRef] [Green Version]
  67. Kaila, B.; Raman, M. Obesity: A review of pathogenesis and management strategies. Can. J. Gastroenterol. 2008, 22, 61–68. [Google Scholar] [CrossRef] [Green Version]
  68. Baretic, M. Obesity drug therapy. Minerva Endocrinol. 2013, 38, 245–254. [Google Scholar]
  69. Yanovski, S.Z.; Yanovski, J.A. Long-term drug treatment for obesity: A systematic and clinical review. JAMA 2014, 311, 74–86. [Google Scholar] [CrossRef]
  70. Klebanov, S.; Astle, C.M.; DeSimone, O.; Ablamunits, V.; Harrison, D.E. Adipose tissue transplantation protects ob/ob mice from obesity, normalizes insulin sensitivity and restores fertility. J. Endocrinol. 2005, 186, 203–211. [Google Scholar] [CrossRef] [PubMed]
  71. Sennello, J.A.; Fayad, R.; Pini, M.; Gove, M.E.; Fantuzzi, G. Transplantation of wild-type white adipose tissue normalizes metabolic, immune and inflammatory alterations in leptin-deficient ob/ob mice. Cytokine 2006, 36, 261–266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Bluher, M. Adipose tissue dysfunction in obesity. Exp. Clin. Endocrinol. Diabetes 2009, 117, 241–250. [Google Scholar] [CrossRef]
  73. Wood, I.S.; de Heredia, F.P.; Wang, B.; Trayhurn, P. Cellular hypoxia and adipose tissue dysfunction in obesity. Proc. Nutr. Soc. 2009, 68, 370–377. [Google Scholar] [CrossRef] [Green Version]
  74. Minteer, D.; Marra, K.G.; Rubin, J.P. Adipose-derived mesenchymal stem cells: Biology and potential applications. Adv. Biochem. Eng. Biotechnol. 2013, 129, 59–71. [Google Scholar] [PubMed]
  75. Cao, M.; Pan, Q.; Dong, H.; Yuan, X.; Li, Y.; Sun, Z.; Dong, X.; Wang, H. Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice. Stem Cell Res. Ther. 2015, 6, 208. [Google Scholar] [CrossRef] [Green Version]
  76. Lee, C.W.; Hsiao, W.T.; Lee, O.K. Mesenchymal stromal cell-based therapies reduce obesity and metabolic syndromes induced by a high-fat diet. Transl. Res. 2017, 182, 61–74.e8. [Google Scholar] [CrossRef]
  77. Liu, G.Y.; Liu, J.; Wang, Y.L.; Liu, Y.; Shao, Y.; Han, Y.; Qin, Y.R.; Xiao, F.J.; Li, P.F.; Zhao, L.J.; et al. Adipose-Derived Mesenchymal Stem Cells Ameliorate Lipid Metabolic Disturbance in Mice. Stem Cells Transl. Med. 2016, 5, 1162–1170. [Google Scholar] [CrossRef] [PubMed]
  78. Yoshimura, K.; Shigeura, T.; Matsumoto, D.; Sato, T.; Takaki, Y.; Aiba-Kojima, E.; Sato, K.; Inoue, K.; Nagase, T.; Koshima, I.; et al. Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates. J. Cell Physiol. 2006, 208, 64–76. [Google Scholar] [CrossRef] [PubMed]
  79. Marlatt, K.L.; Ravussin, E. Brown Adipose Tissue: An Update on Recent Findings. Curr. Obes. Rep. 2017, 6, 389–396. [Google Scholar] [CrossRef] [PubMed]
  80. Teijeiro, A.; Garrido, A.; Ferre, A.; Perna, C.; Djouder, N. Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice. Nat. Metab. 2021, 3, 496–512. [Google Scholar] [CrossRef] [PubMed]
  81. Finlin, B.S.; Memetimin, H.; Zhu, B.; Confides, A.L.; Vekaria, H.J.; El Khouli, R.H.; Johnson, Z.R.; Westgate, P.M.; Chen, J.; Morris, A.J.; et al. The beta3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. J. Clin. Investig. 2020, 130, 2319–2331. [Google Scholar] [CrossRef]
  82. Van Marken Lichtenbelt, W.D.; Vanhommerig, J.W.; Smulders, N.M.; Drossaerts, J.M.; Kemerink, G.J.; Bouvy, N.D.; Schrauwen, P.; Teule, G.J. Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 2009, 360, 1500–1508. [Google Scholar] [CrossRef] [Green Version]
  83. Yao, X.; Salingova, B.; Dani, C. Brown-Like Adipocyte Progenitors Derived from Human iPS Cells: A New Tool for Anti-obesity Drug Discovery and Cell-Based Therapy? Handb. Exp. Pharm. 2019, 251, 97–105. [Google Scholar]
  84. Kishida, T.; Ejima, A.; Yamamoto, K.; Tanaka, S.; Yamamoto, T.; Mazda, O. Reprogrammed Functional Brown Adipocytes Ameliorate Insulin Resistance and Dyslipidemia in Diet-Induced Obesity and Type 2 Diabetes. Stem Cell Rep. 2015, 5, 569–581. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Yao, X.; Dani, V.; Dani, C. Human Pluripotent Stem Cells: A Relevant Model to Identify Pathways Governing Thermogenic Adipocyte Generation. Front. Endocrinol. 2019, 10, 932. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Poon, K. Behavioral Feeding Circuit: Dietary Fat-Induced Effects of Inflammatory Mediators in the Hypothalamus. Front. Endocrinol. 2020, 11, 591559. [Google Scholar] [CrossRef]
  87. Sohn, J.W. Network of hypothalamic neurons that control appetite. BMB Rep. 2015, 48, 229–233. [Google Scholar] [CrossRef] [PubMed]
  88. Livesey, F.J. A potential link between obesity and neural stem cell dysfunction. Nat. Cell Biol. 2012, 14, 987–989. [Google Scholar] [CrossRef] [PubMed]
  89. Ricci, S.; Viggiano, D.; Cimmino, I.; Perruolo, G.; Cabaro, S.; Liotti, A.; Fiory, F.; Spinelli, R.; Di Carlo, A.; Beguinot, F.; et al. Prep1 Deficiency Affects Olfactory Perception and Feeding Behavior by Impairing BDNF-TrkB Mediated Neurotrophic Signaling. Mol. Neurobiol. 2018, 55, 6801–6815. [Google Scholar] [CrossRef] [Green Version]
  90. Li, J.; Tang, Y.; Purkayastha, S.; Yan, J.; Cai, D. Control of obesity and glucose intolerance via building neural stem cells in the hypothalamus. Mol. Metab. 2014, 3, 313–324. [Google Scholar] [CrossRef]
  91. Ren, Z.; Liu, Y.; Hong, W.; Pan, X.; Gong, P.; Liu, Q.; Zhou, G.; Qin, S. Conditional knockout of leptin receptor in neural stem cells leads to obesity in mice and affects neuronal differentiation in the hypothalamus early after birth. Mol. Brain 2020, 13, 109. [Google Scholar] [CrossRef] [PubMed]
  92. Gonzalez-Perez, O. Neural stem cells in the adult human brain. Biol. Biomed. Rep. 2012, 2, 59–69. [Google Scholar] [PubMed]
  93. Cacialli, P.; Palladino, A.; Lucini, C. Role of brain-derived neurotrophic factor during the regenerative response after traumatic brain injury in adult zebrafish. Neural Regen Res. 2018, 13, 941–944. [Google Scholar] [PubMed]
  94. Platt, F.M.; d’Azzo, A.; Davidson, B.L.; Neufeld, E.F.; Tifft, C.J. Lysosomal storage diseases. Nat. Rev. Dis. Primers 2018, 4, 27. [Google Scholar] [CrossRef] [PubMed]
  95. Parenti, G.; Andria, G.; Ballabio, A. Lysosomal storage diseases: From pathophysiology to therapy. Annu. Rev. Med. 2015, 66, 471–486. [Google Scholar] [CrossRef]
  96. Gheldof, A.; Seneca, S.; Stouffs, K.; Lissens, W.; Jansen, A.; Laeremans, H.; Verloo, P.; Schoonjans, A.S.; Meuwissen, M.; Barca, D.; et al. Clinical implementation of gene panel testing for lysosomal storage diseases. Mol. Genet. Genom. Med. 2019, 7, e00527. [Google Scholar] [CrossRef] [PubMed]
  97. Bellettato, C.M.; Hubert, L.; Scarpa, M.; Wangler, M.F. Inborn Errors of Metabolism Involving Complex Molecules: Lysosomal and Peroxisomal Storage Diseases. Pediatr. Clin. N. Am. 2018, 65, 353–373. [Google Scholar] [CrossRef] [PubMed]
  98. Sun, A. Lysosomal storage disease overview. Ann. Transl. Med. 2018, 6, 476. [Google Scholar] [CrossRef]
  99. McKenna, M.C.; Schuck, P.F.; Ferreira, G.C. Fundamentals of CNS energy metabolism and alterations in lysosomal storage diseases. J. Neurochem. 2019, 148, 590–599. [Google Scholar] [CrossRef]
  100. Marques, A.R.A.; Saftig, P. Lysosomal storage disorders—Challenges, concepts and avenues for therapy: Beyond rare diseases. J. Cell Sci. 2019, 132, jcs221739. [Google Scholar] [CrossRef]
  101. Li, M. Enzyme Replacement Therapy: A Review and Its Role in Treating Lysosomal Storage Diseases. Pediatr Ann. 2018, 47, e191–e197. [Google Scholar] [CrossRef]
  102. Thomas, R.; Kermode, A.R. Enzyme enhancement therapeutics for lysosomal storage diseases: Current status and perspective. Mol. Genet. Metab. 2019, 126, 83–97. [Google Scholar] [CrossRef] [PubMed]
  103. Niyazov, D.; Lara, D.A. Improvement in Cardiac Function with Enzyme Replacement Therapy in a Patient with Infantile-Onset Pompe Disease. Ochsner J. 2018, 18, 413–416. [Google Scholar] [CrossRef] [PubMed]
  104. Case, L.E.; Koeberl, D.D.; Young, S.P.; Bali, D.; DeArmey, S.M.; Mackey, J.; Kishnani, P.S. Improvement with ongoing Enzyme Replacement Therapy in advanced late-onset Pompe disease: A case study. Mol. Genet. Metab. 2008, 95, 233–235. [Google Scholar] [CrossRef] [PubMed]
  105. Parker, R.I.; Barton, N.W.; Read, E.J.; Brady, R.O. Hematologic improvement in a patient with Gaucher disease on long-term enzyme replacement therapy: Evidence for decreased splenic sequestration and improved red blood cell survival. Am. J. Hematol. 1991, 38, 130–137. [Google Scholar] [CrossRef]
  106. Aoki, M.; Takahashi, Y.; Miwa, Y.; Iida, S.; Sukegawa, K.; Horai, T.; Orii, T.; Kondo, N. Improvement of neurological symptoms by enzyme replacement therapy for Gaucher disease type IIIb. Eur. J. Pediatr. 2001, 160, 63–64. [Google Scholar] [CrossRef]
  107. Cho, S.Y.; Lee, J.; Ko, A.R.; Kwak, M.J.; Kim, S.; Sohn, Y.B.; Park, S.W.; Jin, D.K. Effect of systemic high dose enzyme replacement therapy on the improvement of CNS defects in a mouse model of mucopolysaccharidosis type II. Orphanet. J. Rare Dis. 2015, 10, 141. [Google Scholar] [CrossRef] [Green Version]
  108. Wraith, J.E. Limitations of enzyme replacement therapy: Current and future. J. Inherit. Metab. Dis. 2006, 29, 442–447. [Google Scholar] [CrossRef]
  109. Concolino, D.; Deodato, F.; Parini, R. Enzyme replacement therapy: Efficacy and limitations. Ital. J. Pediatr. 2018, 44 (Suppl. S2), 120. [Google Scholar] [CrossRef]
  110. Moore, D.F.; Ries, M.; Forget, E.L.; Schiffmann, R. Enzyme replacement therapy in orphan and ultra-orphan diseases: The limitations of standard economic metrics as exemplified by Fabry-Anderson disease. Pharmacoeconomics 2007, 25, 201–208. [Google Scholar] [CrossRef]
  111. Tomatsu, S.; Sawamoto, K.; Shimada, T.; Bober, M.B.; Kubaski, F.; Yasuda, E.; Mason, R.W.; Khan, S.; Almeciga-Diaz, C.J.; Barrera, L.A.; et al. Enzyme replacement therapy for treating mucopolysaccharidosis type IVA (Morquio A syndrome): Effect and limitations. Expert Opin. Orphan Drugs 2015, 3, 1279–1290. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  112. Parini, R.; Deodato, F. Intravenous Enzyme Replacement Therapy in Mucopolysaccharidoses: Clinical Effectiveness and Limitations. Int. J. Mol. Sci. 2020, 21, 2975. [Google Scholar] [CrossRef] [PubMed]
  113. Beck, M. Emerging drugs for lysosomal storage diseases. Expert Opin. Emerg. Drugs 2010, 15, 495–507. [Google Scholar] [CrossRef]
  114. Parenti, G.; Medina, D.L.; Ballabio, A. The rapidly evolving view of lysosomal storage diseases. EMBO Mol. Med. 2021, 13, e12836. [Google Scholar] [CrossRef] [PubMed]
  115. Nagree, M.S.; Scalia, S.; McKillop, W.M.; Medin, J.A. An update on gene therapy for lysosomal storage disorders. Expert Opin. Biol. Ther. 2019, 19, 655–670. [Google Scholar] [CrossRef] [PubMed]
  116. Leimig, T.; Mann, L.; Martin Mdel, P.; Bonten, E.; Persons, D.; Knowles, J.; Allay, J.A.; Cunningham, J.; Nienhuis, A.W.; Smeyne, R.; et al. Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells. Blood 2002, 99, 3169–3178. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  117. Jin, H.K.; Schuchman, E.H. Ex vivo gene therapy using bone marrow-derived cells: Combined effects of intracerebral and intravenous transplantation in a mouse model of Niemann-Pick disease. Mol. Ther. 2003, 8, 876–885. [Google Scholar] [CrossRef] [PubMed]
  118. Biffi, A.; Capotondo, A.; Fasano, S.; del Carro, U.; Marchesini, S.; Azuma, H.; Malaguti, M.C.; Amadio, S.; Brambilla, R.; Grompe, M.; et al. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J. Clin. Investig. 2006, 116, 3070–3082. [Google Scholar] [CrossRef] [PubMed]
  119. Syres, K.; Harrison, F.; Tadlock, M.; Jester, J.V.; Simpson, J.; Roy, S.; Salomon, D.R.; Cherqui, S. Successful treatment of the murine model of cystinosis using bone marrow cell transplantation. Blood 2009, 114, 2542–2552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  120. Yoshimitsu, M.; Higuchi, K.; Ramsubir, S.; Nonaka, T.; Rasaiah, V.I.; Siatskas, C.; Liang, S.B.; Murray, G.J.; Brady, R.O.; Medin, J.A. Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells. Gene Ther. 2007, 14, 256–265. [Google Scholar] [CrossRef]
  121. Enquist, I.B.; Nilsson, E.; Mansson, J.E.; Ehinger, M.; Richter, J.; Karlsson, S. Successful low-risk hematopoietic cell therapy in a mouse model of type 1 Gaucher disease. Stem Cells 2009, 27, 744–752. [Google Scholar] [CrossRef]
  122. van Til, N.P.; Stok, M.; Aerts Kaya, F.S.; de Waard, M.C.; Farahbakhshian, E.; Visser, T.P.; Kroos, M.A.; Jacobs, E.H.; Willart, M.A.; van der Wegen, P.; et al. Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype. Blood 2010, 115, 5329–5337. [Google Scholar] [CrossRef]
  123. Malatack, J.J.; Consolini, D.M.; Bayever, E. The status of hematopoietic stem cell transplantation in lysosomal storage disease. Pediatr. Neurol. 2003, 29, 391–403. [Google Scholar] [CrossRef]
  124. Sergijenko, A.; Langford-Smith, A.; Liao, A.Y.; Pickford, C.E.; McDermott, J.; Nowinski, G.; Langford-Smith, K.J.; Merry, C.L.; Jones, S.A.; Wraith, J.E.; et al. Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease. Mol. Ther. 2013, 21, 1938–1949. [Google Scholar] [CrossRef] [Green Version]
  125. Holley, R.J.; Wood, S.R.; Bigger, B.W. Delivering Hematopoietic Stem Cell Gene Therapy Treatments for Neurological Lysosomal Diseases. ACS Chem. Neurosci. 2019, 10, 18–20. [Google Scholar] [CrossRef] [Green Version]
  126. Stok, M.; de Boer, H.; Huston, M.W.; Jacobs, E.H.; Roovers, O.; Visser, T.P.; Jahr, H.; Duncker, D.J.; van Deel, E.D.; Reuser, A.J.J.; et al. Lentiviral Hematopoietic Stem Cell Gene Therapy Corrects Murine Pompe Disease. Mol. Ther. Methods Clin. Dev. 2020, 17, 1014–1025. [Google Scholar] [CrossRef]
  127. Dunbar, C.; Kohn, D. Retroviral mediated transfer of the cDNA for human glucocerebrosidase into hematopoietic stem cells of patients with Gaucher disease. A phase I study. Hum. Gene Ther. 1996, 7, 231–253. [Google Scholar] [CrossRef]
  128. Dunbar, C.E.; Kohn, D.B.; Schiffmann, R.; Barton, N.W.; Nolta, J.A.; Esplin, J.A.; Pensiero, M.; Long, Z.; Lockey, C.; Emmons, R.V.; et al. Retroviral transfer of the glucocerebrosidase gene into CD34+ cells from patients with Gaucher disease: In vivo detection of transduced cells without myeloablation. Hum. Gene Ther. 1998, 9, 2629–2640. [Google Scholar] [CrossRef]
  129. Lonnqvist, T.; Vanhanen, S.L.; Vettenranta, K.; Autti, T.; Rapola, J.; Santavuori, P.; Saarinen-Pihkala, U.M. Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis. Neurology 2001, 57, 1411–1416. [Google Scholar] [CrossRef]
  130. Sondhi, D.; Hackett, N.R.; Apblett, R.L.; Kaminsky, S.M.; Pergolizzi, R.G.; Crystal, R.G. Feasibility of gene therapy for late neuronal ceroid lipofuscinosis. Arch. Neurol. 2001, 58, 1793–1798. [Google Scholar] [CrossRef] [Green Version]
  131. Bjoraker, K.J.; Delaney, K.; Peters, C.; Krivit, W.; Shapiro, E.G. Long-term outcomes of adaptive functions for children with mucopolysaccharidosis I (Hurler syndrome) treated with hematopoietic stem cell transplantation. J. Dev. Behav. Pediatr. 2006, 27, 290–296. [Google Scholar] [CrossRef]
  132. Grewal, S.S.; Krivit, W.; Defor, T.E.; Shapiro, E.G.; Orchard, P.J.; Abel, S.L.; Lockman, L.A.; Ziegler, R.S.; Dusenbery, K.E.; Peters, C. Outcome of second hematopoietic cell transplantation in Hurler syndrome. Bone Marrow Transplant. 2002, 29, 491–496. [Google Scholar] [CrossRef] [Green Version]
  133. Vormoor, J.; Ehlert, K.; Groll, A.H.; Koch, H.G.; Frosch, M.; Roth, J. Successful hematopoietic stem cell transplantation in Farber disease. J. Pediatr. 2004, 144, 132–134. [Google Scholar] [CrossRef]
  134. Ehlert, K.; Frosch, M.; Fehse, N.; Zander, A.; Roth, J.; Vormoor, J. Farber disease: Clinical presentation, pathogenesis and a new approach to treatment. Pediatr. Rheumatol. Online J. 2007, 5, 15. [Google Scholar] [CrossRef] [Green Version]
  135. Mynarek, M.; Tolar, J.; Albert, M.H.; Escolar, M.L.; Boelens, J.J.; Cowan, M.J.; Finnegan, N.; Glomstein, A.; Jacobsohn, D.A.; Kuhl, J.S.; et al. Allogeneic hematopoietic SCT for alpha-mannosidosis: An analysis of 17 patients. Bone Marrow Transplant. 2012, 47, 352–359. [Google Scholar] [CrossRef] [Green Version]
  136. Biffi, A.; Montini, E.; Lorioli, L.; Cesani, M.; Fumagalli, F.; Plati, T.; Baldoli, C.; Martino, S.; Calabria, A.; Canale, S.; et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013, 341, 1233158. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  137. Sessa, M.; Lorioli, L.; Fumagalli, F.; Acquati, S.; Redaelli, D.; Baldoli, C.; Canale, S.; Lopez, I.D.; Morena, F.; Calabria, A.; et al. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: An ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 2016, 388, 476–487. [Google Scholar] [CrossRef]
  138. Snyder, E.Y.; Taylor, R.M.; Wolfe, J.H. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 1995, 374, 367–370. [Google Scholar] [CrossRef] [PubMed]
  139. Meng, X.L.; Shen, J.S.; Ohashi, T.; Maeda, H.; Kim, S.U.; Eto, Y. Brain transplantation of genetically engineered human neural stem cells globally corrects brain lesions in the mucopolysaccharidosis type VII mouse. J. Neurosci. Res. 2003, 74, 266–277. [Google Scholar] [CrossRef]
  140. Lacorazza, H.D.; Flax, J.D.; Snyder, E.Y.; Jendoubi, M. Expression of human beta-hexosaminidase alpha-subunit gene (the gene defect of Tay-Sachs disease) in mouse brains upon engraftment of transduced progenitor cells. Nat. Med. 1996, 2, 424–429. [Google Scholar] [CrossRef] [PubMed]
  141. Sidman, R.L.; Li, J.; Stewart, G.R.; Clarke, J.; Yang, W.; Snyder, E.Y.; Shihabuddin, L.S. Injection of mouse and human neural stem cells into neonatal Niemann-Pick A model mice. Brain Res. 2007, 1140, 195–204. [Google Scholar] [CrossRef]
  142. Tamaki, S.J.; Jacobs, Y.; Dohse, M.; Capela, A.; Cooper, J.D.; Reitsma, M.; He, D.; Tushinski, R.; Belichenko, P.V.; Salehi, A.; et al. Neuroprotection of host cells by human central nervous system stem cells in a mouse model of infantile neuronal ceroid lipofuscinosis. Cell Stem Cell 2009, 5, 310–319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Robinson, A.J.; Meedeniya, A.C.; Hemsley, K.M.; Auclair, D.; Crawley, A.C.; Hopwood, J.J. Survival and engraftment of mouse embryonic stem cell-derived implants in the guinea pig brain. Neurosci. Res. 2005, 53, 161–168. [Google Scholar] [CrossRef] [PubMed]
  144. Robinson, A.J.; Zhao, G.; Rathjen, J.; Rathjen, P.D.; Hutchinson, R.G.; Eyre, H.J.; Hemsley, K.M.; Hopwood, J.J. Embryonic stem cell-derived glial precursors as a vehicle for sulfamidase production in the MPS-IIIA mouse brain. Cell Transplant. 2010, 19, 985–998. [Google Scholar] [CrossRef]
  145. Kobolak, J.; Molnar, K.; Varga, E.; Bock, I.; Jezso, B.; Teglasi, A.; Zhou, S.; Lo Giudice, M.; Hoogeveen-Westerveld, M.; Pijnappel, W.P.; et al. Modelling the neuropathology of lysosomal storage disorders through disease-specific human induced pluripotent stem cells. Exp. Cell Res. 2019, 380, 216–233. [Google Scholar] [CrossRef]
  146. Doerr, J.; Bockenhoff, A.; Ewald, B.; Ladewig, J.; Eckhardt, M.; Gieselmann, V.; Matzner, U.; Brustle, O.; Koch, P. Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy. Mol. Ther. 2015, 23, 1519–1531. [Google Scholar] [CrossRef] [Green Version]
  147. Meneghini, V.; Frati, G.; Sala, D.; De Cicco, S.; Luciani, M.; Cavazzin, C.; Paulis, M.; Mentzen, W.; Morena, F.; Giannelli, S.; et al. Generation of Human Induced Pluripotent Stem Cell-Derived Bona Fide Neural Stem Cells for Ex Vivo Gene Therapy of Metachromatic Leukodystrophy. Stem Cells Transl. Med. 2017, 6, 352–368. [Google Scholar] [CrossRef]
  148. Griffin, T.A.; Anderson, H.C.; Wolfe, J.H. Ex vivo gene therapy using patient iPSC-derived NSCs reverses pathology in the brain of a homologous mouse model. Stem. Cell Rep. 2015, 4, 835–846. [Google Scholar] [CrossRef] [Green Version]
Figure 1. Representation of main stem cell approaches in type 1 and type 2 diabetes. Abbreviations: ESCs: embryonic stem cells; MSCs: mesenchymal stem cells; iPSCs: induced pluripotent stem cells.
Figure 1. Representation of main stem cell approaches in type 1 and type 2 diabetes. Abbreviations: ESCs: embryonic stem cells; MSCs: mesenchymal stem cells; iPSCs: induced pluripotent stem cells.
Cells 10 02681 g001
Figure 2. Representation of the main stem cell gene therapy approach for treating lysosomal storage diseases. Abbreviations: HSPCs: hematopoietic stem progenitor cells.
Figure 2. Representation of the main stem cell gene therapy approach for treating lysosomal storage diseases. Abbreviations: HSPCs: hematopoietic stem progenitor cells.
Cells 10 02681 g002
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Ricci, S.; Cacialli, P. Stem Cell Research Tools in Human Metabolic Disorders: An Overview. Cells 2021, 10, 2681. https://doi.org/10.3390/cells10102681

AMA Style

Ricci S, Cacialli P. Stem Cell Research Tools in Human Metabolic Disorders: An Overview. Cells. 2021; 10(10):2681. https://doi.org/10.3390/cells10102681

Chicago/Turabian Style

Ricci, Serena, and Pietro Cacialli. 2021. "Stem Cell Research Tools in Human Metabolic Disorders: An Overview" Cells 10, no. 10: 2681. https://doi.org/10.3390/cells10102681

APA Style

Ricci, S., & Cacialli, P. (2021). Stem Cell Research Tools in Human Metabolic Disorders: An Overview. Cells, 10(10), 2681. https://doi.org/10.3390/cells10102681

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop