Inhibition of growth of Asian keloid cells with human umbilical cord Wharton’s jelly stem cell-conditioned medium

Abstract

Background: Keloid formation occurs in Caucasian, African, and Asian populations and is a severe psychosocial burden on patients. There is no permanent treatment for this problem as its pathogenesis is not properly understood. Furthermore, differences in keloid behavior between ethnic groups are not known. It has been hypothesized that keloids behave like benign tumors because of their uncontrolled growth. The present study evaluated the tumoricidal properties of human Wharton's jelly stem cell-conditioned medium (hWJSC-CM) on fresh Asian keloid cells (AKCs). Methods: Human Wharton's jelly stem cells (hWJSCs) and AKCs were isolated based on our previous methods. hWJSCs and human skin fibroblasts (HSF) (controls) were used to collect hWJSC-CM and HSF-conditioned medium (HSF-CM). AKCs were treated with hWJSC-CM and HSF-CM in vitro and in vivo in a human keloid xenograft SCID mouse model. The inhibitory effect of hWJSC-CM on AKCs was tested in vitro using various assays and in vivo for attenuation/abrogation of AKC tumors created in a xenograft mouse model. Results: qRT-PCR analysis showed that the genes FN1, MMP1, and VCAN were significantly upregulated in AKCs and ANXA1, ASPN, IGFBP7, LGALS1, and PTN downregulated. AKCs exposed to hWJSC-CM in vitro showed significant decreases in cell viability and proliferation, increases in Annexin V-FITC+ cell numbers, interruptions of the cell cycle at Sub-G1 and G2/M phases, altered CD marker expression, downregulated anti-apoptotic-related genes, and upregulated pro-apoptotic and autophagy-related genes compared to controls. When AKCs were administered together with hWJSC-CM into immunodeficient mice there were no keloid tumors formed in 7 mice (n = 10) compared to the untreated control mice. When hWJSC-CM was injected directly into keloid tumors created in mice there were significant reductions in keloid tumor volumes and weights in 30 days.Conclusions: hWJSC-CM inhibited the growth of AKCs in vitro and in xenograft mice, and it may be a potential novel treatment for keloids in the human. The specific molecule(s) in hWJSC-CM that induce the anti-keloid effect need to be identified, characterized, and tested separately in larger preclinical and clinical studies.

Asporin inhibits collagen matrix‐mediated intercellular mechanocommunications between fibroblasts during keloid progression

“…By contrast, compared to normal scars, keloids have many undifferentiated fibroblasts but few α‐SMA + myofibroblasts, 20 collagen synthesis remains very high, and the collagen fibers have formed large, thick bundles that are distanced from each other and lie haphazardly in random orientations 9,19 . These features suggest that keloid scars cannot terminate the wound healing process and therefore continue to grow 12,21,22 . Notably, these features of keloids are uncommon in other soft tissue fibroses such as hypertrophic scars and liver and cardiac fibrosis 20 ; thus, keloid is not a conventional fibrotic disease.…”

Circular RNA CircCOL5A1 Sponges the MiR-7-5p/Epac1 Axis to Promote the Progression of Keloids Through Regulating PI3K/Akt Signaling Pathway

“…Keloids are characterized pathologically by the hyper-proliferation of cells (e.g., fibroblasts) and excessive deposition of extracellular matrix (ECM) (e.g., type I and type III collagen) ( Rippa et al, 2019 ). Keloid-derived fibroblasts, served as the main cellular components in keloid tissues, play a pivotal role in modulating the synthesis and re-modeling of ECM, indicating an association between the continuous aggressive growth and collagen production ( Arjunan et al, 2020 ). Meanwhile, in keloid patients, the systemic balance between fibroblast proliferation and apoptosis is distorted, resulting in the continuous hyperplasia of keloids.…”

Mesenchymal Stromal Cell-Conditioned Medium for Skin Diseases: A Systematic Review

“…Preclinical studies are mainly focused on wound healing (Shin et al, 2015;Lee et al, 2020;Narita et al, 2020;Oh et al, 2020), showing high rates in wound closure. MSC-CM may also be an effective treatment for decreasing hypertrophic scars (Arjunan et al, 2020;Hu et al, 2020), improving flap reperfusion (Mirabella et al, 2012;Cooper et al, 2018;Pu et al, 2019), and treating psoriasis (Seetharaman et al, 2019) and AD . Nevertheless, there was significant variability between studies in the cell source, cell treatment, method of delivery, disease model used to assess efficacy, ways of assessment, and outcome evaluation.…”

“…Nine studies evaluated the potential of MSC-CM in the treatment of hypertrophic scars or avoiding scar formation (Wu et al, 2015;Zhang et al, 2015;Du et al, 2016a,b;Li et al, 2016;Choi et al, 2017;Liu et al, 2018;Arjunan et al, 2020;Hu et al, 2020; Table 5). To obtain CM, MSCs were mainly isolated from human tissues: adipose tissue (Li et al, 2016;Choi et al, 2017;Liu et al, 2018) (33.33%, 3/9), umbilical cord blood (Arjunan et al, 2020), placenta (Du et al, 2016a), and bone marrow (Wu et al, 2015). Murine bone marrow (Hu et al, 2020), murine placenta (Du et al, 2016b), and rabbit adipose tissue (Zhang et al, 2015) were also used.…”

“…CM was used mainly by subcutaneous injection (66.66%, 6/9) (Wu et al, 2015;Du et al, 2016a,b;Li et al, 2016;Liu et al, 2018;Hu et al, 2020). Intralesional (Zhang et al, 2015;Arjunan et al, 2020) and intravenous (Choi et al, 2017) injections were also used. MSC-CM was tested in 97 animals for treating hypertrophic scar and keloids or preventing scar formation.…”