## 4 Discussion  
In this study, we used the scratch assay to show that the migration of HaCaT keratinocytes affected wound closure in the presence of MSC-CM. It was found that wound closure was successfully achieved and covered more rapidly in almost the entire part of MSC-CM when compared to that of the control. This could be attributed to the presence of the high secretion of paracrine factors like chemokines, cytokines, and growth factors from MSC-CM that resulted in strong immunomodulatory and immunoregulatory characteristics promoting wound healing [26, 27, 28]. This feature has been indicated in the previous research that found that CM obtained from BM-MSC significantly accelerated scratch wound closure in L929 fibroblasts and HaCaT keratinocytes, supporting the application of MSC-CM as a therapeutic agent in cutaneous wound healing [26]. Accordingly, the latest study by [PERSON] et al. also found that MSC-CM can be used to improve the quality of wound healing with minimal scar formation [2]. Using CM from MSC culture increases fibroblast and basal cell proliferation, collagen synthesis, and improve vascularization in the process of skin wound healing [9, 11]. In our set of investigations, cell survival and proliferation of HaCaT keratinocyte and HFMSC during wound healing were examined in the presence of different kinds of drugs. We found that UK5099, SLL, LDHA, MSC-CM, caffeine, and CFA could promote the proliferation of HFMSC, but only MSC-CM and CFA could promote the proliferation of the HaCaT keratinocyte. Previous study found that caffe acid produced low cytotoxicity of keratinocytes that can induce cell proliferation and differentiation [22]. Furthermore, another study confirmed that cell proliferation could also be elevated by means of CM from culture MSC [13]. In this study, we found treatment with MSC-CM exhibited the highest cell proliferation in both HFMSC and HaCaT keratinocyte during wound healing. MSC-CM could restore the proliferation and migration of keratinocytes, suggesting that MSC-CM has great potential in therapeutic modality supporting the poor wound-healing conditions and improve the effectiveness of tissue regeneration [29, 30]. It has been known that wounds treated with MSCs not only displayed a sign of skin regeneration, but also showed an improvement in the formation of new skin appendages such as hair follicles and sebaceous glands [3]. The ability of skin to regenerate hair follicles during wound healing has been  
Figure 7: Quantitative evaluation showing the thickness of various skin layers after being treated with MSC-CM: (**a**) epidermal thickness, (**b**) cortical thickness, (**c**) hair follicles number, (**d**) muscle layer thickness, and (**e**) fat layer thickness (\({}^{\star}p<0.05\)). clearly demonstrated in animal models known as wound-induced hair growth (WIHG) [31; 32; 33]. In the present study, areas of the skin of the mice began to appear blue to black after respectively being smeared with MSC-CM, projecting the formation of hair follicles. For the above-mentioned reason, paracrine factors such as cytokines, chemokines, and growth factors secreted by the MSC into the medium may play a key role in activating and stimulating fibroblast proliferation during the wound healing as well as regulating human hair growth [34]. It has been known that vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), keratinocyte growth factor (KGF), angiopoietin-1, erythropoietin, and stromal-derived factor-1 (SDF-1) escalated dermal and epidermal cell proliferation and promoted migration of dermal fibroblasts [9; 24; 35]. Furthermore, these growth factors can enhance angiogenesis and the re-epithelialization process, which might be important to stimulate hair follicle regeneration and maintain hair-inducing activity in vivo [35; 36]. In addition, they are involved in the contraction phase, ending at the last stages of remodeling, leading to wound healing in the absence of scar formation and ultimately increasing hair regeneration [35].