(Mesenchymal) Stem Cell-Based Therapy in Cisplatin-Induced Acute Kidney Injury Animal Model: Risk of Immunogenicity and Tumorigenicity

Table 2

Transplantation of autologous, allogeneic MSCs into the cisplatin-induced animal model.

Recipient (species, strain)	Cisplatin treatment	Stem cell origin (donor)	Stem cell treatment	Route	End	Results: effect of treatment on measured parameters	Cell tracking	Ref.
Rattus norvegicus	D0: 13 mg/kg, ip	Rat BM; modified MSC-hLcn2 (human lipocalin-2); (MSCs, MSC-v, MSCs-hLcn2) MSC-v: v-vector	D2: 1.5 × 10^6 in 0.3 ml PBS	iv	D6; D23	Effect of modified MSCs on microenvironment, which is not favorable for survival of MSCs; D6: no effect of any MSCs group on BUN, Cr; D23: MSCs and MSC-v improved parameters, MSC-hLcn2 even more (blood: ↓ BUN, Cr, KIM-1, cystatin C, αGST, GSTYb1, RPA-1, histology score, ↑ AQP-1, CK-18, ↑ HGF, IGF, FGF, VEGF-1)	No	[27]
Sprague-Dawley	D0: 6 mg/kg, ip	Rat BM (allogeneic)	D1:	iv	D0-D5	Blood: ↓ BUN, Cr; kidney: histology score, ↓ TUNEL, Bax, ↑ PCNA, Bcl-2, ↓ miRNA-146b; Study of underlying molecular mechanisms: miRNA-146b increased in AKI	Live imaging CM-Dil: Labeled cells could localize at the injury site	[28]
Sprague-Dawley	D0: 5 mg/kg, ip	Eat BM (allogeneic)	D1: 5 × 10^6 in 0.5 ml CM	iv/rsc/ia	D4; D7; D11; D30	The route of administration of MSCs have no significant influence on the outcome of AKI; Blood: ↓ BUN, Cr, albumin, ↑ calcium; urine: Cr clearance; Kidney: histology improved, ↓ MDA, ↑ SOD, GSH	BrdU (only rsc route): D11: in the kidney under the capsule, in the interstitium and tubules	[29]
C57BL/6J	D0: 12 mg/kg, ip	Mouse Ad; (Syngen); Control CM; Preconditioned CM	D1: 0.1 ml CM	iv	D3	Effects of CM from AdMSC preincubated in a hypoxic environment (preconditioning); Blood: ↓ N-GAL, Cr, proteins: ↓ IL-1β, IL-6, ≈TNFα; Kidney: ↓KIM-1, HMGB-1; ≈survival	No	[30]
C57BL/6J; C57BL/6-Tg(CAG-EGFP)C14-Y01-M131Osb)-GFP	D0: 17.5 mg/kg, ip	Mouse BM; (Syngen); Unsorted	D3: 1 × 10^6 in 0.2 ml sterile PBS	ro	D10	≈Survival; blood: ≈Cr, BUN; kidney: ≈interstitial fibrosis (Masson), PAS, HE, sirius red, apoptosis, proliferation (almost absent), IGF-1; No effect during the acute phase	GFP, CFSE (flow cytometry, qRT-PCR): No labeled cells observed	[31]
Wistar	D0: 5 mg/kg, ip	Rat BM; (allogenic); Nrf2-MSCs, aden-MSCs (aden-adenoviral mediated)	D1: 2 × 10^6	iv	D3; D6; D8; D11	Modified MSC-Nrf2 (overexpressed Nrf2-nuclear factor erythroid-2 related factor 2); D6-D8: Blood: ↓ BUN, Cr; kidney: histology preventive effects	No	[32]
Sprague-Dawley	D0: 7 mg/kg, ip	Rat fetal kidney SC (allogenic)	D5: 2 × 10^6 in 0.15 ml saline	iv	D8; D12	Blood: ↓ BUN, Cr; kidney: ↓ histology score, ↓ TUNEL, ↑ PCNA, ↑ Capillary density, protein ↑ HIF-1α, VEGF, eNOS	PKH26: D7: renal tubules and capillaries	[33]
Wistar	D0: 6 mg/kg, ip	Rat BM (allogenic)	D1: 2 × 10^6	iv	D7	Comparison of BM MSCs and angiotensin II receptor blocker; Blood: ↓ BUN, Cr; kidney: ↓ proteins TNFα, MCP-1, expression ↓ NFκB, p38-MAPK, casp3, Bax	No	[34]
Sprague-Dawley	D0: 6 mg/kg, ip	Rat BM (allogenic)	D1: 1 × 10^6 in 0.5 ml saline	iv	D4	Therapeutic antiapoptotic mechanisms of action of BM; Blood: ↓ BUN, Cr; urine: ↓ microalbumin, ↑ Cr; Kidney: ↑ PCNA, ↓ TUNEL, histology score	PKH26: D4: peritubular areas, rarely within the tubular epithelium	[35]
C57BL/6J; C57BL/6-TgCAG-ECFP/1Osb/J; GFP expressing	D1: 12 mg/kg, sc	Mouse BM (syngenic)	D0: (3 different routes); 5 × 10^5, iv; 4 × 10^6, ip (microcarriers; 1 × 10^6, sc (laparotomy)	iv/ip/; rsc	D3; D5; D8	Evaluation of organ biodistribution of transplanted MSCs; Blood: ↓ BUN; kidney: histology score independent of the route of MSC delivery; Distribution: 1 h after iv: trapped in the lungs (67.2%), liver (12.5%), spleen (11.4%), and kidney (5.4%); survived longer in renal subcapsular space and peritoneal cavity	Radiolabeled ^111Indium-oxine MSCs, GFP: iv delivery: detected 24 h but not 7 days after transplantation	[36]
F344; n = 5–12; Heminephrectomy	D0: 7 mg/kg, sc	Rat stromal vascular fraction (SVF) from subcutaneous adipose tissue (autologous)	D1: 1 × 10^6	rsc/ ip	D6; D14	SVF can be obtained readily without culturing and may be clinically applicable; Blood: ↓ Cr (D4-D8 peak than the levels return to the baseline); kidney: ↓ TUNEL (medulla only), ↑ VEGF (cortex only), ↑ HGF, ↑ renal capillary velocity (D14), ↑ Ki67; ip administration: no effect; VEGF staining localized mainly around the CFDA^+ cells	CFDA: D14 (only rsc injection): found in the subcapsules, not located in the tubular cell layer nor in the vascular cell layer	[37]
BALB/c (female); n = 9–30	D0: 14.7 mg/kg, sc	Mouse BM; Epo gene-enhanced (allogeneic: male C57BL/6: MHCI^+, MHC-II^−); MSCs/Epo-MSCs	D1: 5 × 10^6 in 0.37 ml RPMI	ip	D4^p; D14	Investigate the beneficial effects of Epo-secreting MSCs; D4: blood: ↓ BUN, ALT in both, ↓ Cr, amylase only in Epo-MSCs; kidney: ↓ Casp3, ↑ Ki-67 in both; D8-14: ↑ survival (67%/44% versus 33%), ↓ BUN only in Epo-MSCs; protective effects in liver, pancreas as well	Y chromosome-specific fragment of 444 bp (PCR of kidney): detected	[38]
HO-1^+/+; HO-1^−/− (C57BL/6xFVB)Fn; n = 10–13	D0: 20 mg/kg, ip	Mouse BM (syngeniec); CM of HO-1^+/+, HO-1^−/−	6 h after cisplatin; 0.2 ml of CM concentrated 10x	ip	D3	CM of HO-1^−/− no effects; CM of HO-1^+/+: ↓ BW loss, blood: ↓ Cr; Kidney: ↓ histology score, casp3	No	[39]
C57Bl/6	D0: 10 mg/kg,; D1: 10 mg/kg, ip	Mouse BM,; mouse Ad (syngeniec)	D2: 2 × 10^5 (BM); 1 × 10^5 (Ad)	iv/ip	D3; D6	↑ survival; blood: ↓ BUN, Cr; kidney: ↑ PCNA, BrdU, ↓ TUNEL; Reduced severity of AKI seen in both BM and Ad and regardless of delivery route (iv/ip).	Y chromosome (fluorescence in situ hybridization); 1 h: detected in the lung, but not in the liver, spleen, or kidney; 24 h and 96 h: not found in the kidney	[16]
Dog, beagles	D0: 5 mg/kg, iv	Dog BM (autologous)	D0: (after cisplatin) 1 × 10^6 in 10 ml saline, cephalic vein	iv	D0-D4	Biochemical analyses, urinalyses, blood picture,; Blood: leukopenia, ↑ BUN, Cr, phosphate,; Kidney: ↑ PCNA, ↓ TNFα, TGF-β, ≈TUNEL, ≈VEGF, histology score, SD-1, HGF; No improvement in the renal function, less fibrotic change in the kidney	SPIO labeled-BM: D4: not seen under MRI; but detected by Prussian blue staining of kidney sections (only glomeruli but not renal tubules)	[40]
Rhesus Macaca mulatta monkey	D0: 5 mg/kg, iv	Monkey BM (autologous)	D4: 5 × 10^6 or M6: 5 × 10^6	ia	M1, M3, M6 (M9)	Preventive versus stable model (application of MSCs 6 months after cisplatin); Preventive: blood: ≈BUN, Cr, K, Na; kidney: ↓ histology score; stable: ≈ BUN, Cr, K, Na; kidney: ≈histology score; No adverse effects on the spleen, lungs, and liver observed; hepatic sinusoidal dilatation and congestion in the control group after 9 months (1/15)	No	[41]
Monkey; Macaque mulatta	D0: 5 mg/kg, iv	Monkey BM (autologous)	D4: 5 × 10^6 cells/kg; BW	ia	D4; D10; D14; D21; D28; D84	Blood: ↓ BUN, Cr, urine: ↑ Cr, urea clearance, ≈Na, K, no protenuria, polyuria up to D84; ↑ Foxp3^+ T regulatory (Treg) cells at D28 (transplantation group only), interstitial fibrosis and matrix (Schiff staining); Biochemical improvement but no significant histological improvement	SPIO labeled-BM: seen under MRI (2 h, 24 h) and detected by Prussian blue staining (D1, D2, D28) of kidney sections (mostly localized in the glomeruli)	[42]

N: number of animals per group; D: day; BM: bone marrow; Ad: adipose tissue; CM: culture media; GFP: green fluorescent protein reporter gene. Unsorted BM MSC: mixture of hematopoietic cells, mesenchymal stem cells, lymphoid and myeloid progenitors. sc: subcutaneously; rsc: subcapsular; ia: intra-arterial; iv: intravenously; ro: retro-orbital injection; M: month; TUNEL: transferase-mediated dUTP nick end labeling assay; PCNA: proliferating cell nuclear antigen; PKH26: lipophilic fluorescent dye; GFR: glomerulat filtration rate; IHC: immunohistochemistry; BW: body weight; CFDA SE: carboxyfluorescein diacetate, succinimidyl ester; SPIO: superparamagnetic iron oxide; ^p-peak (of BUN and Cr levels).