Adipose-derived stem cells: Pathophysiologic implications vs therapeutic potential in systemic sclerosis

Table 1 Summary of the main therapeutic effects of fat grafting and stromal vascular fraction/adipose-derived stem cells in preclinical models of systemic sclerosis-like pulmonary and skin fibrosis

Animal model	Treatment	Results	Ref.
Bleomycin-induced lung fibrosis mouse model	Human ADSC administration	Amelioration of cuboidal alveolar epithelial cell hyperplasia, alveolar duct infiltration, septal thickening and tissue fibrosis. Suppression of epithelial cell apoptosis and reduction of TGF-β expression	Lee et al[47], 2014
Aged mouse model of bleomycin-induced lung fibrosis	Single intravenous injection of allogeneic ADSCs	Attenuation of lung and skin fibrosis	Rubio et al[48], 2018
Bleomycin-induced lung injury rat model	Intratracheal administration of autologous ADSCs	Prevention of further aggravation of lung damage at day 15 after disease induction	Uji et al[49], 2015
Bleomycin-induced lung fibrosis mouse model	Administration of ADSCs from aged and young mice	Decreased pulmonary fibrosis, oxidative stress, and markers of apoptosis only in animals receiving young ADSCs at day 21 after bleomycin instillation	Tashiro et al[50], 2015
Bleomycin-induced skin sclerosis model in nude mice	Local subcutaneous injections of human micro-fat enriched with SVF	Decrease in the established dermal fibrosis and increase in local vascularization	Serratrice et al[51], 2014
Bleomycin-induced skin sclerosis model in nude mice	Human ADSC-assisted local subcutaneous lipotransfer	Reduced TGF-β1 and type III collagen expression	Chen et al[52], 2018
Bleomycin-induced skin fibrosis mouse model	Subcutaneous injection of autologous ADSCs	Amelioration of dermal fibrosis	Chen et al[53], 2017
Bleomycin-induced scleroderma and Scl-cGVHD mouse models	Intravenous administration of allogeneic ADSCs	Attenuation of skin and lung fibrosis	Okamura et al[54], 2020
Bleomycin-induced skin fibrosis mouse model	Intradermal injection of allogeneic ADSCs	Provision of dendritic cell-derived signals improved survival and effectiveness of therapeutically delivered ADSCs	Chia et al[55], 2016
HOCl-induced mouse model of diffuse SSc	Intravenous injection of healthy murine and human ADSCs	Decrease in skin and lung fibrotic and pro-inflammatory markers	Maria et al[56], 2016

SVF: Stromal vascular fraction; ADSCs: Adipose-derived stem cells; SSc: Systemic sclerosis; TGF-β: Transforming growth factor-β; Scl-cGVHD: Sclerodermatous chronic graft-versus-host disease; HOCl: Hypochlorous acid.

Table 2 Summary of fat grafting and adipose-derived stem cell-based treatments in systemic sclerosis

No. of patients	Follow-up period	Results (face)	Ref.
1	-	Autologous fat grafting improved perioral aesthetic appearance and mouth opening	Ho-Asjoe et al[58], 1996
20	3 mo	Autologous fat grafting increased interincisal distance, oral perimeter and induced skin neovascularization	Del Papa et al[60], 2015
14	6 mo	Autologous fat grafting improved perioral skin sclerosis, facial pain, mouth opening and sicca syndrome	Sautereau et al[61], 2016
7	12 mo	Autologous fat grafting improved SSc-related microstomia and microcheilia	Blezien et al[62], 2017
16	3 mo	Autologous fat transfer significantly improved mouth opening capacity	Gheisari et al[63], 2018
1	-	Autologous fat grafting enriched with PRP improved skin trophicity	Daumas et al[13], 2020
6	3 mo	The combined use of autologous lipoaspirate and PRP improved buccal rhyme, skin elasticity, and vascularization of the perioral and malar areas	Virzì et al[64], 2017
6	12 mo	Local injection of autologous ADSCs in combination with a hyaluronic acid solution led to arrest of local disease progression, regression of dyschromia, better sensitivity, increase in skin softening and erythema reduction	Scuderi et al[23], 2013
10	12 mo	Both autologous fat grafting and ADSC-enriched hyaluronic acid gel improved mouth opening and interincisal distance	Onesti et al[65], 2016
62	6-53 mo	Autologous ADSC-enriched lipotransfer significantly improved mouth function, facial volumetric appearance and psychological outcome	Almadori et al[3], 2019

ADSCs: Adipose-derived stem cells; SSc: Systemic sclerosis; PRP: Platelet-rich plasma.

Table 3 Summary of fat grafting and stromal vascular fraction-based treatments in systemic sclerosis

No. of patients	Follow-up period	Results (hands)	Ref.
13	9.4 to 24.3 mo	Autologous fat implantation led to significant pain relief and decrease in the number, duration, and severity of Raynaud’s phenomenon cold attacks	Bank et al[66], 2014
9	12 wk	Autologous fat grafting was effective in accelerating the healing process of DUs and led to a significant reduction in hand pain and need of pharmacological therapy	Bene et al[67], 2014
15	6 mo	Autologous SVF injections led to prompt disappearance of local ischemic pain, rapid DU healing and improvement in nailfold capillaroscopy abnormalities	Del Papa et al[68], 2015
38	8 wk	Autologous fat grafting induced DU healing, restoration of the capillary bed and a rapid resolution of local ischemic pain	Del Papa et al[14], 2019
12	6 mo	Injection of autologous SVF proved to be safe, well tolerated and beneficial in terms of pain, grasping capacity, finger edema, Raynaud’s phenomenon, DU outcome and quality of life	Granel et al[69], 2015
12	12 mo	The effects recorded by Granel et al[69] proved to be long lasting, as they persisted 1 yr after SVF injection	Guillaume-Jugnot et al[70], 2016
12	22-30 mo	The effects recorded by Granel et al[69] were still very encouraging even at 22 and 30 mo after treatment	Daumas et al[72], 2017
1	-	Autologous SVF subcutaneous injections had beneficial effects on digital necrosis, ulceration, gangrene and impaired wound healing	Song et al[73], 2017

SVF: Stromal vascular fraction; DU: Digital ulcer.