Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

Table 1 Summary of studies reporting significant differences in the urine composition of myalgic encephalomyelitis/chronic fatigue syndrome patients (P ≤ 0.1)

Ref.	Population studied/study design	Diagnosis criteria	Technique	Metabolites with increased levels				Metabolites with decreased levels
Erasmus et al[19], 2019	31 high CFS (patients) (31 F, 0 M). 39 low CFS (control) (39 F, 0 M). Age range, median and mean age NA	NA	H-NMR	Salicylic acid						P = 0.06
				Glucose
				Acetaminophen						P = 0.08
				Acetaminophen-glucuronide
Zhang et al[10], 2019	105 CFS (65 F, 40 M). 97 DD (56 F, 41 M). 190 HC (69 F, 121 M). Age range 20-49. Median and mean age NA	NA	H-NMR	M: Taurine						P < 0.01
				M: Tyrosine
				M: Leucine
				M: Valine
				M: Isoleucine
				M: Aspartate
				M: Ethylmalonate
				M: Lactate
				M: Threonine
				M: Trans-Aconitate
				M: 2-Aminohippurate
				M: N-Phenylacetylglycine
				M: N-Acetylaspartate
				M: Thymol
				B: Dimethylamine
				B: Histidine
				B: 4-Aminohippurate
				B: Hippurate
				B: Glutamine
				B: Isocitrate						P > 0.05
				B: 1-Methylnicotinamide
				B: N-Acetylglutamine
				B: Creatinine
				F: Isobutyrate
				F: Lysine
				F: Alanine
				F: Hypoxanthine
				F: Fucose
				F: N,N-dimethylglycine
				F: Urea
				F: Carnosine
				F: 3-Hydroxymandelate
				F: Indole-3-lactate
McGregor et al[20], 2019	11 ME/CFS (11F, 0 M) Mean age 30.9. 25 HC (24 F, 1 M). Mean age 33. 6	Canadian criteria	H-NMR	Mannitol	P < 0.001		Acetate			P < 0.001
							Urea
				Methylhistidine	P < 0.01		Pyruvate
Chi et al[21], 2018	98 CFS (77 F, 21 M). Age range 21-69. Median age 43. 99 HC (76 F, 23 M). Age range 19-65 yr. Median age 39 yr. Mean age: NA	United States centers	LC-MS	AE: Methyladenosine	P < 0.05		BE: Indoleacetaldehyde			P < 0.05 or P < 0.01
							BE: Phytosphingosine
							BE: Pyroglutamic acid
							BE: Creatinine
							AE: Acetylcarnitine
							AE Capric acid
							AE: Corticosterone
				AE: Creatinine			AE: Levonorgestrel
							AE: Pantothenic acid
							AE: Pyroglutamic acid
							AE: Xanthosine
							AE: Xanthurenic acid
							AE: Nonanedioic acid
Ruiz-Núñez et al[14], 2018	98 CFS (77 F, 21 M). Age range 21-69 yr. Median age 43 yr. 99 HC (76 F, 23 M). Age range 19-65 yr. Median age 39 yr. Mean age: NA	Fukuda criteria	LC-MS	NA			Nutritional factor		Urinary Iodine	P < 0.001
McGregor et al[11], 1996	20 CFS (16 F, 4 M). Age range 17-58 yr. Mean age 39.4 yr. 45 HC (32 F, 13 M). Age range 12-74 yr. Mean age 37.1 yr. Median age NA	CDC criteria	GC-MS	Aminohydroxy-N-methylpyrrolidine CFSUM1		P < 0.00003	CFSUM2			P < 0.0007
				Tyrosine		P < 0.02	Alanine			P < 0.005
				β-alanine
				Aconitic acid		P < 0.05	Glutamic acid			P < 0.02
				Succinic acid

AE: After exercise; B: Both; BE: Before exercise; F: Female; GC-MS: Gas chromatography-mass spectrometry; H-NMR: Proton nuclear magnetic resonance; HC: Healthy control; LC-MS: Liquid chromatography-mass spectrometry; M: Male; ME: Myalgic encephalomyelitis; NA: Not available.

Table 2 Summary of studies reporting significant differences in body fluids composition of fibromyalgia patients (P ≤ 0.05)

Ref.	Population studied/study design	Diagnosis criteria	Sample	Technique	Metabolite with increased levels					Metabolite with decreased levels
Menzies et al[23], 2020	20 FMS (20 F, 0 M). 20 HC (20 F, 0 M). Mean age in both groups 41.9 yr. Age range and medium age NA	ACR 1990 criteria	Plasma	LC-MS	Amino acid metabolism	Taurine		P < 0.001		Energy metabolism		2-hydroxyglutarate	P < 0.001
						Methionine sulfoxide
						Anthranilate
					Lipid metabolism	Lysophosphocholines (16:0)
						Lysophosphocholines (18:0)
						Lysophosphocholines (20:4)		P = 0.001				Alpha-ketoglutaric acid	NA
						Lysophosphocholines (22:6)
						Lysophosphocholines (18:1)		P = 0.003
						Lysophosphocholines (16:1)		P = 0.007
Caboni et al[24], 2014	22 FMS (22 F, 0 M). Age range 27-72 yr. Mean age 52 yr. 21 HC (21 F, 0 M). Age range 27-67 yr. Mean age 50 yr. Median age NA	ACR criteria	Plasma	LC-Q-TOF/MS	1-hexadecanoyl-sn-glycero-3-phosphocholine [PC (16:0)]			NA		NA
					1-tetradecanoyl-sn-glycero-3-phosphocholine [PC (14:0)]
Clos-Garcia et al[25], 2019	105 FMS (73 F, 32 M). 54 HC (26 F, 28 M). Age range and mean and medium age NA	ACR 2010 criteria	Serum	UPLC-MS	Ornithine			NA		Platelet activating factor (PAF-16)			NA
					L-arginine
					Nε-Methyl-L-lysine
					L-glutamate
					Asymmetric dimethylarginine (ADMA)
					l-threonine/DL-homoserin
					L-glutamine
Hackshaw et al[26], 2013	10 FMS (9 F, 1 M). Mean age 50 yr. 10 OA (7 F, 3 M). Mean age 65 yr. 10 RA (9 F, 1 M). Mean age 60 yr. Age range and median age NA	ARC criteria	Blood	UHPLC/MS/MS	Trans-urocanate			NA		NA			NA
					Asparagine
					Heme
					Cysteine–glutathione disulfide
					Glucose
					Pyruvate
					Nicotinamide adenine dinucleotide (NAD+)
Malatji et al[27], 2019	17 FMS (17 F, 0 M). 62 HC (62 F, 0 M), 11 CF, 10 CO, 41 CN (age range 18-22 yr). Median and mean age: NA	ACR 1990 criteria	Urine	GC-MS	3-D-Ribohexonic acid								P = 0.0000089
					Sorbose								P < 0.00001
					Threonic acid
					Erythropentonic acid
					2-Keto-1-gluconic acid
					2-hydroxyglutaric acid								P = 0.000013
					Arabinose								P = 0.000017
					2-D-3,5-DHPL								P = 0.000019
					2,3,4-Trihydroxybutyl-L								P = 0.000021
					Phosphoric acid								P = 0.00011
					Glutaric acid
					Oxalic acid
					Rhamnose
					Tagatose								P = 0.00024
					4-HBA								P = 0.00109
					Malic acid								P = 0.024
Malatji et al[28], 2017	18 FMS (18 F, 0 M). 41 HC (41 F, 0 M), 11 FR, 10 AM, 20 YHC (age range 18-22 yr). Median and mean age NA	ARC 1990 criteria	Urine	QE-MS	Gut microbiome		Succinic acid		P = 0.0001		NA
							Lactic acid		P = 0.0044
							Hippuric		P = 0.09
					Osmolytes		Taurine		P = 0.0007
							TMAO		P = 0.006

ACR: American College of Rheumatology; B: Both; CFS: chronic fatigue syndrome; F: Female; GC-MS: Gas chromatography-mass spectrometry; HC: Healthy control; LC-MS: Liquid chromatography-mass spectrometry; LC-Q-TOF/MS: Liquid chromatography quadrupole time-of-flight mass spectrometry; M: Male; NA: Not available; QE-MS: Q exactive mass spectrometer; TMAO: Trimethylamine N-oxide; UPLC-MS: Ultra-performance liquid chromatography-mass spectrometry.

Table 3 Effects of disease-conditioned medium on in vitro cultured stem cells

Ref.	Disease/condition	Conditioned medium/culture supernatant	Target cultured cells	Results/effects
Raimondo et al[30], 2019	Multiple myeloma (MM)	Exosomes from MM.1S cell line. Exosomes from bone marrow	hTERT-MSC (human telomerase reverse transcriptase stromal cell line)	Osteoclastogenesis (Osteoclast formation). Blockade of osteogenic differentiation of MSC with increased IL-8 expression
Bougaret et al[31], 2017	Obesity-associated increased risk of metastasis in breast cancer post-menopausal patients	Supernatant of MCF-7 cells cocultured with mature adipocytes	Human umbilical vein endothelial cells (HUVECs)	Increased HUVEC cell proliferation, endothelial tube formation, migration, IL-6 levels and decrease in Leptin and VEGFR HUVEC receptors
Bai et al[32], 2016	Trichinella spiralis skeletal muscle infection	Supernatant of murine macrophage cell line J774A.1 infected with ML-ESP	Murine myoblast cell line C2C12	Avoid formation of myotubes by decreased MyoD, myogenin and MyHC protein expression affecting the differentiation of myoblasts. Suppresses the cell cycle influencing p21 and D1 protein expression
Kozakowska et al[33], 2015	Diabetes-associated angiogenesis deficiency	Supernatant of C2C12 myoblasts overexpressing HO-1 or a luciferase gene (control)	Intramuscular injection in mice	Improved skeletal muscle regeneration after ischemia by increased neovascularization with lower number of granulocytes and higher proportion of lymphocytes
Wobus et al[34], 2015	Breast cancer	Supernatant of MFC-7, MDA-MB231 breast carcinomas with respect to MCF-10 (control)	Primary Mesenchymal Stromal Cells (MSC) and MSC cell line SCP-1	Modulate genes belonging to proliferation and differentiation. Downregulation of chemokine receptor CXCL12 expression
Cabbage et al[35], 2014	Atherosclerosis	Supernatant of the macrophage cell line (RAW 264.7) inoculated with Chlamydia pneumoniae	BSMC (bovine aortic smooth muscle cells) and perivascular Sca-1+, CD31-, CD45- cells from apoE-/- mouse aortas	Accelerate the conversion of smooth muscle cells to calcifying cells. Increase the production of collagen II causing osteochondrocytic phenotypes
Fasslrinner et al[36], 2012	Graft vs host disease/Inflammation	MLR supernatant (Mixed Lymphocyte Reaction) from PBMCs	Mesenchymal stromal cells (MSC) from the bone marrow	Decrease in the population doubling compared to control. Increased IL-8, IL-6 and Ang-1 levels. Induced osteogenic differentiation and suppress adipogenic differentiation
Zhao et al[37], 2007	Amyotrophic lateral sclerosis (ALS)	SOD1-G93A ALS mice CNS extracts	hMSC (human mesenchymal stem cell)	Morphological change from fibroblast to neuron phenotype without detectable apoptosis and death. Delay in proliferation of hMSC due to increased differentiation rate
Vaisman et al[38], 1996	Granulopoiesis in Anorexia Nervosa	Plasma and supernatant of cultured PBMCs	Bone marrow GM-CSF (granulocyte macrophage colony forming cells)	Decreased numbers of GM-CFS
Roodman et al[39], 1992	Paget’s disease	Supernatant of cultured Paget’s nonadherent bone marrow mononuclear cells	Bone marrow cells from healthy donors	Increased MNC (multinucleated cell) formation and IL-6 levels

BMI: Body mass index; CNS: Central nervous system; hADSC: Human adipose-derived stem cells; HO-1: Heme oxygenase; ML-ESP: Excretory-secretory products released by the muscle-larvae from Trichinella spiralis; PBMC: Peripheral blood mononuclear cell; VEGFR: Vascular endothelial growth factor receptor.