Can Stem Cells Repair Scar Tissue

Abstract

Scars are the normal upshot of wound repair and involve a co-ordinated inflammatory and fibrotic process. When a scar does not resolve, uncontrolled chronic inflammation tin persist and elicits excessive scarring that leads to a range of abnormal phenotypes such as hypertrophic and keloid scars. These pathologies result in significant impairment of quality of life over a long menstruation of time. Existing treatment options are generally unsatisfactory, and at that place is mounting interest in innovative jail cell-based therapies. Despite the interest in mesenchymal stalk cells (MSCs), there is yet to be a human clinical trial that investigates the potential of MSCs in treating abnormal scarring. A synthesis of existing testify of animal studies may therefore provide insight into the barriers to human application. The aim of this PRISMA systematic review was to evaluate the effectiveness of MSC transplantation in the handling of hypertrophic and keloid scars in in vivo models. A total of eleven case-command studies were identified that treated a total of 156 subjects with MSCs or MSC-conditioned media. Ten studies assessed hypertrophic scars, and one looked at keloid scars. All studies evaluated scars in terms of macroscopic and histological appearances and about incorporated immunohistochemistry. The included studies all found improvements in the in a higher place outcomes with MSC or MSC-conditioned media without complications. The studies reviewed support a function for MSC therapy in treating scars that needs further exploration. The transferability of these findings to humans is express by factors such equally the reliability and validity of the disease model, the need to identify the optimal MSC cell source, and the outcome measures employed.

Introduction

Wounds to the skin are caused past mechanical, thermal, and chemical trauma. Scars (or cicatrix) are the normal effect of wound repair and involve a co-ordinated inflammatory and fibrotic process. Eventually, the scars remodel and become soft, flat, pale, and unobtrusive. When a scar does non resolve, persistent chronic inflammation can crusade excessive scarring that pb to a range of aberrant phenotypes which clinically manifest equally hypertrophic and keloid scars.

Hypertrophic scars bear upon nearly one in 5 people who suffer from burns and the hazard of scarring increases with the time taken to heal (Chipp et al. 2022). They tin also occur following incisional closure, a standard part of surgical procedures. Typically appearing inside 2 months of injury, the illness procedure can be protracted and therefore carries significant societal and financial cost over a long period of time (Gangemi et al. 2008). Keloid scars impact tens of millions of people worldwide, and there is strong show of a significant genetic predisposition (Bayat et al. 2003; Santos-Cortez et al. 2022). In dissimilarity to hypertrophic scars, keloid scars tin can appear much subsequently post-injury and are characterised by extension beyond the original expanse of the trauma. Ultimately, hypertrophic and keloid scars result in significant impairment of quality of life (Bock et al. 2006). In addition to corrective consequences, these abnormal scars can take functional implications including restricted mobility, hurting, and pruritus (Bijlard et al. 2022; Lee et al. 2004).

Excess scarring may persist and often recurs after multiple interventions (Darzi et al. 1992; Gauglitz et al. 2022). Near patients suffer from neuropathic pain and pruritus, and the mainstay of handling is bourgeois therapy (Argirova et al. 2006). However, existing handling options are generally unsatisfactory for patients and doctors alike. In particular, surgery, which is mainly focused on scar excision, has a very loftier recurrence rate whether used solitary or in combination with depot steroids (Berman et al. 2009; Furtado et al. 2022; Wilson 2022). Strategies aimed at scar growth suppression include topical treatments such as retinoic acid, imiquimod, and corticosteroid injections (Jacob et al. 2003; Janssen De Limpens 1980). These remedies tend to demonstrate just brusk-term efficacy (Berman et al. 2009; Cação et al. 2009). Repeated steroid injections are notwithstanding efficacious. Pressure therapy and silicone gel foam or sheets stand out equally clinically useful and widely used measures both therapeutically and preventatively (Ai et al. 2022; Kim et al. 2022). Modalities such as radiotherapy, cryotherapy, and lasers take either loftier failure rates, and/ or carry risk of agin events, not to mention high cost (Manuskiatti and Fitzpatrick 2002; Puri and Talwar 2009; Song et al. 2022; Steinstraesser et al. 2022). Therefore, there is mounting interest in innovative methods to treat hypertrophic and keloid scars. Emerging studies have therefore taken a different arroyo and focussed on cell-based therapies such equally mesenchymal stem cells (MSCs) (Fung et al. 2022).

MSCs are developed multipotent stromal cells that can exist readily harvested from various sites such every bit os marrow, adipose, and umbilical tissue (Baksh et al. 2007; Khan et al. 2008). MSCs can be expanded ex vivo and cultured under specific conditions to promote particular cellular effects. Due to their low immunogenicity, MSCs are oft transplanted allogeneically for the treatment of inflammatory conditions (Kabat et al. 2022). MSCs exert their anti-inflammatory and anti-fibrotic paracrine effects via the chemokines and microvesicles that they secrete (Badiavas et al. 2003; Horwitz and Dominici 2008; Rani et al. 2022). Excessive scarring involves undesired inflammation that results in deposition of immature extracellular matrix (ECM) by fibroblasts and myofibroblasts (Barallobre-Barreiro et al. 2022). Whilst tissue native MSCs play a key role in potentiating this process, there is evidence to suggest that transplanted MSCs are instead able to attenuate inflammation and promote a return to homeostasis (Chen et al. 2009; Ren et al. 2008). MSCs may reach this by mediating macrophage course switch from a proinflammatory M1 to anti-inflammatory M2 phenotype (Cho et al. 2022). MSCs also have the potential to negatively modulate ECM deposition, perchance via promoting a T-jail cell response that results in the downregulation of TGF-β1, a central regulator of collagen synthesis (Huang et al. 2022; Spiekman et al. 2022).

Despite the interest in MSCs, at that place is yet to exist a human clinical trial that investigates the potential of MSCs in treating excessive scarring. A synthesis of existing evidence of animate being studies volition therefore provide insight into the barriers to human application. The aim of this systematic review was to evaluate the effectiveness of MSC transplantation in the treatment of hypertrophic and keloid scars in in vivo models.

Materials and methods

A literature search was performed using PubMed, Web of Science, and Cochrane Database from conception to May 2022. The following search terms were used: ((((((((MSC) OR Mesenchymal Stalk Cell) OR Mesenchymal Stromal Prison cell) OR Multipotent Stem Cell) OR Multipotent Stromal Jail cell) OR Stalk Cell)) AND ((Keloid) OR Hypertrophic)) AND Scar.

We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included case control, cohort studies, example series, and randomised controlled trials (Moher et al. 2009). A full of 1098 studies were subjected to the inclusion/exclusion criteria, yielding a final 11 studies for qualitative analysis (Fig. i). Studies that evaluated MSC or MSC-conditioned media transplantation equally therapies were included. Studies that assessed in vivo models were included. Studies of all design were included. Literature reviews, systematic reviews, and case reports were excluded simply were reverse-reference searched to maximise yield. Studies with merely in vitro experiments were excluded. All included studies were published in the English linguistic communication, and all unpublished, inaccessible, and retracted literature were excluded. CB and KT carried out the search independently. Chance of bias was assessed by AH and JS using the SYRCLE RoB tool (Table 1; Fig. 2) (Hooijmans et al. 2022).

Fig. one

Catamenia diagram of search strategy

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Table 1 Summary of level of bias of individual studies

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Fig. 2

Overall risk of bias

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Results

A total of eleven studies were identified (Tables 2, 3, and 4) (Domergue et al. 2022; Foubert et al. 2022; Hu et al. 2022, 2022; Li et al. 2022; Liu et al. 2022, 2022; Yates et al. 2022; Yates et al. 2022; Zhang et al. 2022). A full of 156 subjects were treated with MSCs or MSC-conditioned media. There were no pregnant complications reported in any of the studies. Ten studies assessed the effectiveness of MSCs or MSC-conditioned media in treating hypertrophic scars and one in keloid scars. All studies were example control studies.

Table ii MSC isolation and characterisation

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Tabular array 3 Characteristics of studies observing MSC furnishings on scar formation from wounds

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Table 4 Characteristics of studies observing MSC effects on formed scars

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MSC isolation and characterisation

Six studies used bone marrow MSCs: two of murine origin (Hu et al. 2022, 2022), two of man origin (Yates et al. 2022; Yates et al. 2022), one of rabbit origin (Liu et al. 2022), and i study included both man and rabbit origin MSCs (Liu et al. 2022). Five of the studies that employed bone marrow MSCs harvested cells by needle aspiration from either the tibia, femur or posterior iliac crest (Hu et al. 2022, 2022; Liu et al. 2022; Liu et al. 2022; Yates et al. 2022). One study, by Yates et al. (Yates et al. 2022) used bone marrow MSCs derived from an immortalised cell line. V studies utilised adipose MSCs: three of human (Domergue et al. 2022; Li et al. 2022; Liu et al. 2022), 1 of porcine (Foubert et al. 2022) and one of rabbit origin (Zhang et al. 2022). Three studies experimented MSCs from inguinal fat pad or redundant tissue from surgical operations (Foubert et al. 2022; Liu et al. 2022; Zhang et al. 2022). Domergue et al. (2016) extracted MSCs by dermolipectomy and Li et al. (2016) past liposuction. Whilst all the studies applied flow cytometry to characterise MSCs, only four satisfied the International Society for Cellular Therapy (ISCT) criteria for defining MSCs by also performing tri-lineage differentiation (Dominici et al. 2006; Hu et al. 2022, 2022; Yates et al. 2022; Yates et al. 2022). Five studies performed bi-lineage differentiation only (Li et al. 2022; Liu et al. 2022, 2022; Liu S. et al. 2022; Zhang et al. 2022).

MSC handling and commitment

Most studies passaged MSCs at least three times. Only two studies used MSCs from earlier passage; Domergue et al. (2016) used passage one, and Foubert et al. (2017) did not passage the cells at all. Interestingly, 2 studies harvested MSCs across the eighth passage (Hu et al. 2022, 2022). Studies transplanted varying concentrations of MSCs but at similar volumes of around 200 μl. Two studies administered 1000 μl (Li et al. 2022; Liu et al. 2022), whilst three studies dispensed less than 100 μl of MSCs (Domergue et al. 2022; Liu. et al. 2022; Yates et al. 2022). Yates et al. (Yates et al. 2022) did not specify the quantity given. The routes of MSC administration were highly variable. Eight of the eleven studies delivered MSCs or MSC-conditioned media by subcutaneous injection. Of these, four studies specified further; two injected iv points of the wound (Domergue et al. 2022; Liu et al. 2022), one injected into the eye of each wound (Zhang et al. 2022), and the fourth delivered MSCs past circumferential intradermal injection into each wound (Liu et al. 2022). Of the remaining three studies, one report delivered MSCs onto the wound via an droplets (Foubert et al. 2022), one applied the MSCs to fill the wound defect (Yates et al. 2022), and i injected MSCs intra-arterially (Liu et al. 2022). Five of the xi studies utilised MSC-conditioned media (Hu et al. 2022, 2022; Li et al. 2022; Liu et al. 2022; Zhang et al. 2022). 2 studies used chemokine receptor 3 (CXCR3) knockout mice, which are known to scar excessively when wounded (Yates et al. 2022; Yates et al. 2022). Four studies employed internal controls by injecting MSCs on the contralateral side of the animal subject (Foubert et al. 2022; Hu et al. 2022; Yates et al. 2022; Zhang et al. 2022). Five studies utilised Dulbecco'due south modified Eagle media (DMEM) (Hu et al. 2022, 2022; Li et al. 2022; Liu et al. 2022; Zhang et al. 2022), and iii applied phosphate buffer solution (PBS) as controls (Domergue et al. 2022; Liu et al. 2022; Liu et al. 2022). Other control groups comprised lactated Ringer'southward solution (LR), hyaluronic acid (HA), and no handling every bit a control (Foubert et al. 2022; Yates et al. 2022; Yates et al. 2022). The majority of studies followed up wound progression for at least 28 days.

Disease model

Viii studies evaluated the effectiveness of MSCs in preventing hypertrophic scar germination (Table 3), and iii studies examined MSC therapy on formed scars. In the latter, one study assessed keloid scars and included four subjects. Six studies assessed murine, iv used rabbit, and 1 utilised a porcine subject. All the induced wounds were total dermal-thickness just varied in size and location, with the majority being round dial wounds inflicted on the dorsum of murine subjects. Four studies inflicted full-thickness punch wounds on the ears of rabbit subjects (Hu et al. 2022; Liu et al. 2022; Liu et al. 2022; Zhang et al. 2022). Three studies (Tabular array 4) created full-thickness skin wounds on homo peel samples which were then xenografted onto murine subjects (Domergue et al. 2022; Hu et al. 2022; Liu et al. 2022).

Treatment outcomes and complications

All studies assessed wounds in terms of macroscopic appearance and histology with about including immunohistochemistry. No complications were reported by any of the studies. Gross appearance was evaluated in all studies using high-resolution photography, and all studies reported positive improvements in various measured parameters in the MSC-treated group compared with controls. Eight studies described reduced scar hypertrophy in the MSC-treated group compared with controls (Domergue et al. 2022; Foubert et al. 2022; Hu et al. 2022, 2022; Li et al. 2022; Yates et al. 2022; Yates et al. 2022; Zhang et al. 2022). Two studies reported that MSC-treated subjects attenuated hypertrophic scar formation (Liu et al. 2022; Liu et al. 2022). One report evaluated keloid size and institute greater scar shrinkage following handling (Liu et al. 2022). Several studies assessed collagen characteristics using assays of collagen gel contraction (Hu et al. 2022), collagen deposition (Foubert et al. 2022; Hu et al. 2022), and collagen content (Domergue et al. 2022). All studies reported reduced collagen deposition and reduced collagen contracture in the MSC-treated group compared with controls. Two studies assessed fibroblast apoptosis. Hu et al. (2020) found increased fibroblast apoptosis by staining for caspase-7. Liu et al. (2018) measured the presence of phosphatidylserine in the outer layer of the phospholipid bilayer as a surrogate marker of apoptosis and found no alter in the MSC-treated group compared with control. Another written report used TUNEL (last deoxynucleotidyl transferase dUTP nick end labelling) staining to assess MSC apoptosis and found that a significant proportion of MSCs underwent apoptosis afterwards administration onto a wound (Liu et al. 2022). 3 of the 11 studies assessed scar thickness, with two using digital planimetry (Foubert et al. 2022; Liu et al. 2022) and one using ultrasonography (Zhang et al. 2022). All studies reported reduced scar tissue height and hardness. Yates et al. (2017), by staining caspase-three with a fluorescent probe, found reduced caspase-3, suggesting improved fibroblast survival following MSC co-transplantation.

Discussion

Although the outcomes reported in this review by and large favour MSC transplantation in treating excessive scarring and did not written report complications, it is difficult to describe reliable conclusions due to the heterogeneity of the studies. This arises from various aspects; there was significant variability in the cell source, cell treatment, method of delivery, and the disease model used to appraise efficacy. Almost studies demonstrated moderate to high overall risk of bias as they were aiming to different and more specific questions relevant to MSC utilize. However, this systematic review provides a useful summary and helps inform futurity study pattern.

The properties of MSCs can vary according to the cell source. Consistent with the existing literature, most of our studies examined adipose MSCs (AMSCs) and os marrow MSCs (BMMSCs) (Kabat et al. 2022). Both of these cell sources have their relative advantages for use in treating scars. AMSCs offer a greater capacity to proliferate ex vivo compared with other jail cell sources (Peng et al. 2008) and therefore may be suitable for large scale off-the-shelf preparations at greater toll-effectiveness. They may also be more abundant, less invasive to harvest, and are frequently bachelor as medical waste in many cosmetic surgery procedures. BMMSCs may represent a less heterogenous cell population (Liu et al. 2022) but exhibit senescence at earlier passage (Couch et al. 2022). An of import consideration is that the anti-inflammatory backdrop of MSCs could differ by cell source. Particular studies suggest that AMSCs may be superior in promoting an M1 to M2 phenotype transition in macrophages that favour resolution of inflammation (Heo et al. 2022). This is relevant equally macrophages are a key mediator of the pathogenic process of excessive scarring (Feng et al. 2022; Hesketh et al. 2022). In addition, sure MSCs demonstrate a greater ability to engraft onto lesions and can therefore produce more sustained effects (Burk et al. 2022). Ane study in this review compared human and rabbit prison cell sources and found both cell sources to be as efficacious (Liu et al. 2022). Harvesting MSCs from animals rather than humans may be more than convenient but the immunogenic consequences of xenogeneic transplantation with human recipients are yet to exist thoroughly investigated. Although heterogeneity of MSC origin and culture status among the included studies may affect the reliability of conclusions drawn from them, it is reassuring that positive furnishings were observed across multiple cell sources. This indicates that MSCs regardless of origin have the potential to treat hypertrophic and keloid scars. Future studies should aim to identify the best prison cell source for treating excessive scarring.

Significant heterogeneity was also observed betwixt the studies in terms of culture weather condition and handling delivery methods. The literature suggests that pre-conditioning MSCs with inflammatory cytokines may serve to promote an anti-inflammatory MSC phenotype (Saldaña et al. 2022). Similarly, following co-civilisation with fibroblasts, a cell type prevalent in inflamed scars, MSCs express greater levels of anti-inflammatory cytokines (Suzuki et al. 2022). This suggests that treating MSCs in conditions cogitating of the scar environs might potentiate their effectiveness when used in transplantation. Conversely, serum-free culture conditions appear to enhance the anti-fibrotic properties of MSCs in vivo (Yoshida et al. 2022). This may represent a potential claiming as the optimal civilisation protocol should promote an anti-fibrotic response without compromising the anti-inflammatory properties of MSCs. I way of circumventing this could be to stimulate MSCs under a particular set of culture conditions, and so harvesting the conditioned media that contains bioactive extracellular vesicles (EVs). The MSCs can then exist resuspended and grown under a different prepare of culture weather to promote secretion of dissimilar bioactive substances. Indeed, several studies in our review showed that a jail cell-free handling using MSC-conditioned media tin can be effective (Hu et al. 2022, 2022; Li et al. 2022; Zhang et al. 2022).

On the other paw, it is difficult to identify the best MSC delivery method. MSCs injected into the apportionment appear to engraft well into wounds (Deng et al. 2005), but carry a risk of interacting with cytokines and drugs nowadays in the serum, which may alter MSC function (Javorkova et al. 2022). In dissimilarity, MSCs injected directly into a lesion of interest could delocalise speedily (Burk et al. 2022) and therefore still have the potential to exert off-site effects (Devine et al. 2003). Although there were no complications reported in any of the studies in this review, several factors have the potential to influence MSC biodistribution and therefore clinical efficacy following administration. It has been reported that pulmonary complications relating to Four administration of MSCs could be dependent on the cell break formulation (Deak et al. 2022). Other studies suggest that following initial localisation in the lungs post-obit systemic administration, MSCs can dwelling house to areas of inflammation (Rustad and Gurtner 2022). Although useful in cases of isolated peel pathology, undesired offsite effects may be observed in cases of other underlying systemic inflammation (Gholamrezanezhad et al. 2022). There is also evidence to testify that the migration and proliferation of MSCs at skin wounds can be a function of MSC expression of adhesion molecules including junction adhesion molecule A (JAM-A) (Wu et al. 2022). Likewise, chemokines such as CCR7 likewise announced to promote MSC migration to skin wounds (Sasaki et al. 2008). For the purposes of treating scars, it appears that local administration may exist preferable, with recent studies demonstrating rubber in animals via subcutaneous (Tappenbeck et al. 2022) and topical (Beyazyildiz et al. 2022) routes. Robust experiments that compare methods of MSC delivery in treating scars should address this ambiguity.

It remains uncertain whether interpretations fatigued from animal models of excessive scarring can be transferred directly to inform treatment in humans. Most of the studies in this review assessed the effects of MSCs on the caste of hypertrophy during the scarring procedure. This probably does not replicate the homo affliction where patients typically present with a fully formed scar. Nevertheless, it may inform whether MSCs can exist implemented at the time of injury (in high risk patients) or shortly after or in conjunction with surgical scar treatment as a means of preventing master or recurrent hypertrophic or keloid scars. Genetic models of hypertrophic scarring may confer high reproducibility. There are existing gain-of-function models such as the Tight Peel two mouse which showroom increased fibrosis following injury (Long et al. 2022), presumably due to increased collagen III alpha-1 expression (Long et al. 2022). Instead of a gain-of-function model, the two studies by Yates et al. (Yates et al. 2022; Yates et al. 2022) captured in this review utilised a previously validated knockdown model by targeting the CXCR3 gene (Yates et al. 2022). Whilst both methods may exist informative for in vivo studies of hypertrophic scarring, they practise not reflect the pattern of genetic predisposition in humans (Zhu et al. 2022), and the knock-down target does non correlate with known protective genetic variants (Sood et al. 2022). It is suggested that concomitantly xenografting human being skin cells into the wound may improve the validity of the mouse burns model by promoting a more extensive scar phenotype (Ibrahim et al. 2022; Momtazi et al. 2022). Nevertheless, this could be confounded by the immunogenic furnishings of xenografting pare onto an immunocompetent mouse (Racki et al. 2022). Nevertheless, the studies in this review that conducted xenografting of human pare into mouse defects did not observe graft rejection (Domergue et al. 2022; Hu et al. 2022; Liu et al. 2022).

Another issue relates to the fourth dimension-course of scar pathogenesis. Most mouse models develop mature hypertrophic or keloid scarring within days to weeks later burn injury and weeks to months after incisional injury (Kim et al. 2022), unlike the longer fourth dimension course of human being illness. In humans, excessive scarring can occur later months (Gangemi et al. 2008), with biomolecular evidence of active disease at up to a yr later (Van Der Veer et al. 2022). There is testify in the literature to support the potential employ of the Cherry-red Duroc porcine model, which develops scarring over months instead, and therefore meliorate recapitulates the human procedure (Harunari et al. 2006; Zhu et al. 2003, 2004). We captured 1 study by Foubert et al. (2017) that was able to utilise this model in guild to undertake an extended follow-upwardly period of six months, when active scar growth was still observed. Whilst all of the studies demonstrated sustained benefit and did non report recurrence up to the finish point of follow-up, keloid and hypertrophic scars are known in humans to recur after many months to years post-obit successful handling (Furtado et al. 2022). Therefore, the short lifespan of murine models may non let sufficient longitude to appraise whether the benefits of MSC therapy is sustained. Future studies of porcine models with long follow-up periods may facilitate this.

In order to fully exploit the beneficial effects of MSCs in treating scars, it is important to establish a dose-response relationship. The studies in this review varied significantly in the amount of MSC or MSC-conditioned media used, only all reported positive outcomes. Only one written report examined the furnishings of varying the dose of MSC-conditioned media used and constitute a dose-response relationship (Li et al. 2022). It is unclear whether the same relationship may be observed in treatment with MSCs of varying concentration and there is evidence in models of ischaemic injury that higher doses of MSCs do non ever confer greater therapeutic benefit (Yavagal et al. 2022). Therefore, a relevant futurity written report might aim to determine the maximum tolerated dose (MTD) for MSCs in treating keloid and hypertrophic scars. The method of delivery might influence this, as appropriate dosage for intravenous injection may be derived from the weight of the subject area, whereas intralesional commitment may require the volume of the scar of interest to be calculated. Digital planimetry, every bit employed by several studies here, may exist a viable method of achieving this (Foubert et al. 2022; Liu et al. 2022). Ascertaining the MTD will besides inform safe dosages that practise not evoke adverse effects (Karussis et al. 2022). Six studies in this review treated scars with MSCs, four studies used conditioned media, and 1 compared the two. There has been an emerging trunk of evidence to support the use of conditioned media, which contains bioactive extracellular vesicles (EVs) that may be the agile therapeutic ingredient of MSCs (Furuta et al. 2022). As a cell-free therapy, it is possible that EVs are less immunogenic and may therefore exist more suitable for big-scale product from allogeneic sources (Monguió-Tortajada et al. 2022).

Outcome measures utilised by in vivo studies tin can limit their transferability to humans. Whilst reduction in scar size and improvement in histological advent may reflect the cosmetic benefits of treatment, it is unclear how it affects scar symptoms. Every bit hurting and pruritis are the main symptoms of hypertrophic and keloid scars (Lee et al. 2004), functional assessments in animals may be crucial earlier undertaking human trials. For example, there are well-validated and quantifiable behavioural measures such as voice that reverberate pain in mice (Kurejova et al. 2022). Assessing the degree of physical activity such as time spent earthworks (Shepherd et al. 2022) could potentially reveal the functional implications of contractures resulting from scars, although this could be dependent on the position of the lesion. Aside from looking to reduce the corporeality of scarring, at that place is a range of symptoms that tin be acquired past excessive scarring, and and so separate studies may be required to evaluate the differential benefits of MSC therapy and to determine a personalised approach co-ordinate to the specific symptom.

Determination

The present review suggests that mesenchymal stem cell (MSC) therapy tin exist an effective method of treating hypertrophic and keloid scars across a range of cell sources and creature models and does not cause significant complications. However, there is inadequate high-level evidence of in-human studies to support clinical efficacy in humans. There are several areas that demand to be addressed before proceeding to human trials. This includes the identification of a reliable, reproducible, and validated animal model, and a standardised method of MSC delivery to allow a dose-response relationship to be established. The similar positive results observed to date with MSCs and MSC-conditioned media are encouraging and should exist explored further past assessing the efficacy of MSC-derived extracellular vesicles, as this volition comport significant implications for cost-effectiveness in treating humans at a population scale.

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Author notes

1. Christine Bojanic and Kendrick To equally contributed to this work.

Affiliations

1. Plastic & Reconstructive Surgery Department, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United kingdom of great britain and northern ireland

   Christine Bojanic & Charles Thou. Malata

2. Division of Trauma and Orthopaedics, Section of Surgery, Addenbrooke'south Hospital, Academy of Cambridge, Cambridge, Great britain

   Kendrick To, Chiliad. T. Matthew Seah & Wasim Khan

3. Schoolhouse of Clinical Medicine, University of Cambridge, Cambridge, UK

   Adam Hatoum & Jessie Shea

4. Cambridge Breast Unit of measurement, Addenbrooke'south Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

   Charles M. Malata

5. School of Medicine, Anglia Ruskin University, Cambridge & Chelmsford, UK

   Charles M. Malata

Contributions

CB and KT contributed equally equally first author. The study was designed and supervised by KT, WK, and CMM. JS and AH carried out study quality assessment. KTS conducted qualitative information synthesis. All authors contributed significantly and were involved in editing, reviewing, and blessing the manuscript.

Respective author

Correspondence to Wasim Khan.

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Bojanic, C., To, K., Hatoum, A. et al. Mesenchymal stem cell therapy in hypertrophic and keloid scars. Cell Tissue Res 383, 915–930 (2021). https://doi.org/10.1007/s00441-020-03361-z

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• Received: 04 June 2022

• Accepted: 19 November 2022

• Published: 02 January 2022

• Issue Engagement: March 2022

• DOI : https://doi.org/10.1007/s00441-020-03361-z

Keywords

• Mesenchymal stem cells
• Scar
• Pain
• Wound healing
• Wound regeneration

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