Advances in mesenchymal stem cell therapy for lupus nephritis

Table 1 Classifications, histopathology and therapeutic approaches for lupus nephritis

Classifications	Histopathology	Therapeutic approaches
Minimal mesangial LN (class I)	Only mesangial immune deposits; no light microscopic abnormalities	Hydroxychloroquine. Low-level proteinuria-immunosuppressive treatment guided by extrarenal manifestations of SLE. Nephrotic syndrome-maintenance combination therapy with low-dose glucocorticoid and another immunosuppressive agent
Mesangial proliferative LN (class II)	Mesangial hypercellularity or mesangial matrix expansion. A few isolated subepithelial or subendothelial deposits on IF or EM
Focal LN (class III)	< 50% glomeruli affected. Active or inactive endocapillary or extracapillary glomerulonephritis, always segmental (< 50% glomerular tuft). Subendothelial deposits on EM	Hydroxychloroquine. Initial therapy-glucocorticoids plus MPAA/low-dose intravenous cyclophosphamide/belimumab and either MPAA or low-dose intravenous cyclophosphamide/MPAA and a CNI. Maintenance therapy-low-dose glucocorticoids plus MPAA
Diffuse LN (class IV)	≥ 50% glomeruli affected. Endocapillary with or without extracapillary glomerulonephritis. Subendothelial deposits on EM
Lupus membranous nephropathy (class V)	Diffuse thickening of the glomerular capillary wall. Mesangial involvement. Subepithelial immune deposits	Hydroxychloroquine. Low-level proteinuria-RAS blockade, immunosuppressive treatment guided by extrarenal manifestations of SLE. Nephrotic syndrome-RAS blockade, immunosuppressive treatment with glucocorticoid and one other agent
Advanced sclerosing LN (class VI)	Global sclerosis in > 90% glomeruli	General management

LN: Lupus nephritis; IF: Immunofluorescence; EM: Electron microscopy; SLE: Systemic lupus erythematosus; MPAA: Mycophenolic acid analogs; CNI: Calcineurin inhibitor; RAS: Renin-angiotensin system.

Table 2 Comparison of mesenchymal stem cell sources and their characteristics[9-11]

Source	Method of procurement	Advantages	Disadvantages
BM-MSCs	Isolated from BM aspiration	Potential to differentiate into hepatocytes, much like AD-MSCs; short culture time	Invasive and painful procedure; use of anesthesia; cell yield, longevity and potential for differentiation diminishes with donor age
UC-MSCs	Isolated from the placenta, amnion and UC blood after birth	Avoidance of invasive procedures; abundance; reliability of sample collection; lack of transmission of herpes viruses; higher expansion and engraftment capacity than BM-MSCs	UC-MSCs may not have adipogenic potential; less osteogenesis potential
AD-MSCs	Isolated from liposuction, lipoplasty or lipectomy materials	Easy to access; abundant throughout the body; secrete cytokines and growth factors with anti-inflammatory, antiapoptotic and immunomodulatory properties; lower risk of immune rejection because of the absence of MHC-II antigen expression	Inferior osteogenic and chondrogenic potential in comparison to BM-MSCs
DT-MSCs	Isolated from tooth extraction or root canal surgery materials	Accessible source; higher frequency of colony forming cells from dental pulp compared to those from BM	Difficult and invasive procedure; ectomesenchymal and periodontal tissues affect MSC properties
MSC-Exos	Isolated from the cultural supernatant of MSCs using high speed centrifugation	Easy to obtain in large quantities from immortalized cells; lower immunogenicity; less possibility of graft rejection; higher safety profile due to the nanoscale size	Fast clearance of MSC-Exos limit their long-term therapeutic effects; heterogeneity of MSC-Exos due to different culture conditions and cell passages

BM-MSCs: Bone marrow-derived mesenchymal stem cells; BM: Bone marrow; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; UC: Umbilical cord; AD-MSCs: Adipose tissue-derived mesenchymal stem cells; DT-MSCs: Dental tissue-derived mesenchymal stem cells; MSC-Exos: Mesenchymal stem cell-derived exosomes; MSC: Mesenchymal stem cell; MHC-II: Class II major histocompatibility complex.

Table 3 Clinical studies of mesenchymal stem cell therapy for lupus nephritis

MSCs (sources, timing, dose)	Study design	Sample size (n), LN/SLE	Follow up (months)	Safety and adverse effects	Outcomes	Ref.
UC-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	15/16, refractory LN	3-28	Severe nausea (1/16). No treatment-related mortality or other adverse events	SLEDAI scores decreased gradually during 6 months follow-up (10/16). Anti-dsDNA antibody decreased significantly at 3 months (13/16) and gradually decreased after 6 months (3/16). Reduced proteinuria and improved eGFR during 6 months follow-up (8/16) and further improved during long-term follow-up (2/16)	Sun et al[58], 2010
BM-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	15/15, refractory LN	12-36	No serious adverse events. No GVHD. Upper respiratory tract infections	Decreased SLEDAI score at 12 months follow-up (12/13). Lower titers of anti-dsDNA at 3 months follow-up (11/15). Reduced 24 hours proteinuria at 12 months follow-up (12/12)	Liang et al[57], 2010
BM-MSCs/UC-MSCs (single or double i.v. injection 1 × 106 cells/kg)	Dose comparison trial	50/58, refractory LN	12-48	One death in double transplantation group. Upper respiratory tract infection, intestinal infection, herpes zoster infection, pulmonary tuberculosis considered non transplantation related	Complete remission (16/30) in single transplantation group and (8/27) in multiple transplantation group during 4 years follow-up. Decreased SLEDAI score during 3 years follow-up. Decreased anti-dsDNA titer during 2 years follow-up. Reduced proteinuria and improved eGFR during 3 years follow-up	Wang et al[18], 2012
BM-MSCs/UC-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	73/87, refractory LN	48	Death (5/87), diarrhea (2/87), herpesvirus infection (2/87), agranulocytosis and oral fungus infection (1/87), pulmonary tuberculosis (1/87), bone fracture (1/87), myocardial infarction (1/87) considered non transplantation related	Overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83), 31% at 2 years (12/39), 42% at 3 years (5/12), and 50% at 4 years (3/6). Rates of relapse were 12% (10/83) at 1 year, 18% (7/39) at 2 years, 17% (2/12) at 3 years, and 17% (1/6) at 4 years. The overall rate of relapse was 23% (20/87)	Wang et al[59], 2013
UC-MSCs [double i.v. injection (1 week apart) 1 × 106 cells/kg]	Single arm	38/40, active LN	12	Well tolerated. Herpesvirus infection, death, and tuberculosis infection with no relation to transplantation	Decreased SLEDAI score at 12 months follow-up. Decreased anti-dsDNA titer at 12 months follow-up. Reduced proteinuria and improved eGFR at 6 months follow-up. Four patients relapse at 12 months follow-up	Wang et al[22], 2014
BM-MSCs/UC-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	81/81, active and refractory LN	12	Death (4/87), enteritis and diarrhea (2/87) with no relation to transplantation	Survival rate was 95 % (77/81) during the 12 months follow-up. Complete remission rate was 17.5% (14/80) at 3 months, 18.2% (14/77) at 6 months, and 23.4% (18/77) at 12 months. 60.5% renal remission, 22.4% renal flare. Decreased SLEDAI score and BILAG score, improved GFR at 12 months follow-up	Gu et al[54], 2014
UC-MSCs [double i.v. injection (1 week apart) 2 × 108 cells/each]	Randomized double-blind, placebo-controlled trial	18/18, WHO class III or IV LN	12	Leukopenia, pneumonia, subcutaneous abscess	Remission rate in the UC-MSCs group was 75% (9/12), compared to 83% (5/6) in the placebo group. No effect of UC-MSCs above standard immunosuppression	Deng et al[56], 2017
UC-MSCs (single i.v. injection 1 × 106 cells/kg)	Single arm	21/21, refractory LN	6	No treatment-related mortality or other adverse events	Decreased SLEDAI score at 6 months follow-up. Reduced proteinuria, maintained eGFR 6 months follow-up. Up-regulation of peripheral blood CD1c+ DCs and serum FLT3L	Yuan et al[39], 2019
AD-MSCs (single i.v. injection, 2 × 106 cells/kg)	Single arm. Phase I clinical trial	9/9, biopsy-proven refractory LN	12	No allergic reaction or other adverse effects	Decreased SLEDAI score. Decreased anti-dsDNA titer at the first month. Reduced proteinuria and improved eGFR at the first 3 months	Ranjbar et al[25], 2022

MSC: Mesenchymal stem cell; LN: Lupus nephritis; SLE: Systemic lupus erythematosus; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; i.v.: Intravenous; SLEDAI: Systemic lupus erythematosus disease activity index; anti-dsDNA: Anti-double stranded DNA; eGFR: Estimated glomerular filtration rate; BM-MSCs: Bone marrow-derived mesenchymal stem cells; GVHD: Graft-vs-host disease; BILAG: British Isles Lupus Assessment Group; WHO: World Health Organization; DCs: Dendritic cells; FLT3L: FMS-related tyrosine kinase 3 ligand; AD-MSCs: Adipose tissue-derived mesenchymal stem cells.