Systematic review and network meta‐analysis of mesenchymal stem cells in treating diabetic skin ulcers in animal models

Abstract

Background

Diabetic cutaneous ulcers often pose considerable challenges in the healing process. These challenges stem from factors including inadequate perfusion of the ulcer's surrounding environment, persistent inflammation, tissue damage and microbial proliferation. The existing standard treatment modalities prove insufficient in fully addressing the complex pathogenesis of these ulcers. As a novel approach, researchers are exploring cellular therapies employing mesenchymal stem cells (MSCs) for the treatment of diabetic skin ulcers. MSCs are readily found in various tissues, including bone marrow, adipose tissue, placenta, amniotic membrane, amniotic fluid and umbilical cord. However, the optimal source of MSCs for effectively treating diabetic skin ulcers remains a topic of ongoing discussion.

Methods

We conducted a comprehensive search of Embase, PubMed and Web of Science databases, spanning from their inception to November 2022. Subsequently, we rigorously screened the literature following predetermined inclusion and exclusion criteria and evaluated the quality of the selected studies using the SYRCLE scale. Finally, the included literature underwent analysis, employing the Bayesian school of thought‐based R language. To ensure transparency and accountability, we registered this study with PROSPERO's International Systematic Review Prospective Registry, with the Registration ID: CRD42023387421.

Results

We included a total of 11 articles in our analysis, all of which were randomized controlled studies involving 218 animal models. Among these studies, two utilized adipose‐derived MSCs, six employed bone marrow‐derived MSCs, one utilized amniotic membrane‐derived MSCs and three utilized umbilical cord‐derived MSCs. Our network meta‐analysis results revealed that there were no statistically significant differences in the healing rates of diabetic skin ulcers among MSCs derived from amniotic membrane, adipose tissue, umbilical cord and bone marrow on days 7–8, 10–12 and 12–14. Notably, according to the probability ranking table, the most effective treatment for diabetic wounds was found to be amniotic membrane‐derived MSCs.

Conclusion

There was no statistically significant difference in the efficacy of MSCs derived from amniotic membrane, adipose, umbilical cord and bone marrow in the treatment of diabetic skin ulcers during the short‐term observation period, and the probability ranking graphs indicate that amniotic membrane‐derived MSCs may be the best choice for the treatment of diabetic skin ulcers.

1. INTRODUCTION

Diabetes mellitus is a prevalent metabolic disorder characterized by a high incidence rate. Prolonged exposure to elevated glucose levels induces a range of neurological, microvascular and macrovascular complications in the body. Additionally, it diminishes the immune response, leading to impaired wound healing. This chronic condition is often further exacerbated by tissue ischemia or persistent stress. ¹ , ² Compared to the normal wound healing process, diabetic wounds present significant challenges due to various complex factors, including impaired migration of keratinocytes and fibroblasts, dysregulated secretion of chemokines and growth factors, abnormal inflammatory responses and inhibited angiogenesis. ³ , ⁴ , ⁵ , ⁶ Presently, the treatment of diabetic ulcers typically involves a multidisciplinary approach. ⁷ Internal therapeutic interventions primarily focus on managing blood glucose levels, adjusting antibiotic regimens, enhancing microcirculation and employing neurotrophic drugs. ⁸ Surgical measures involve debridement, the application of appropriate dressings and wound repair following infection control. ⁹ However, these current treatment methods have their limitations, often yielding unsatisfactory results. In recent years, novel treatment modalities, such as electrical stimulation therapy, oxygen therapy and stem cell technology, have shown promising outcomes in laboratory and early clinical applications. These innovative approaches hold the potential to become the preferred choice for managing diabetic refractory wounds.

Stem cells possess the remarkable capability of multidirectional differentiation, coupled with immunomodulatory and paracrine functions, rendering them highly conducive to comprehensive wound repair. ¹⁰ Stem cells encompass both embryonic and adult categories. Embryonic stem cells, as totipotent stem cells, exhibit robust proliferative capacity but lower differentiation maturity. While well suited for addressing diabetic wounds characterized by mixed lesions, their clinical utility is constrained by ethical, legal and immune rejection concerns. In contrast, adult stem cells, classified as pluripotent stem cells, offer a promising avenue. They include various types such as haematopoietic stem cells, bone marrow mesenchymal stem cells (MSCs), adipose MSCs, umbilical cord MSCs and amniotic membrane MSCs. Adult stem cells hold substantial potential for the treatment of diabetic skin ulcers, primarily due to their exemption from ethical and legal constraints, diminished immune rejection risk and reduced tumorigenicity. ¹¹

MSCs were initially discovered in the bone marrow and subsequently identified in various tissues, including the umbilical cord, placenta, adipose tissue, amniotic fluid and others. ¹² MSCs possess the capacity to influence different phases of wound healing to varying extents, thereby expediting the overall wound recovery process. ¹³ In vivo studies have demonstrated that during the inflammatory phase, MSCs migrate into the wound site in response to inflammatory factors and chemokines released by injured tissues and inflammatory cells. In this context, MSCs exert anti‐inflammatory and anti‐apoptotic effects through their differentiation into wound repair cells and their paracrine mechanisms. ¹⁴ , ¹⁵ , ¹⁶ In the proliferative phase, MSCs contribute to accelerated wound healing by promoting angiogenesis through paracrine actions and exerting antimicrobial effects. ¹⁷ In the remodelling phase, MSCs facilitate wound plasticity by regulating the ratio of collagen types I and III within the wound. ¹⁸ , ¹⁹

Recent research, both domestically and internationally, has affirmed that MSCs derived from various tissues hold the potential for enhancing the healing of diabetic skin ulcers. ²⁰ However, a comprehensive understanding of the distinct mechanisms underlying the actions of MSCs from different sources and their relative efficacy in diabetic wound treatment requires further investigation. ²¹ This paper is dedicated to exploring the mechanisms and effectiveness of MSCs derived from different tissues in the context of diabetic ulcer treatment.

2. MATERIALS AND METHODS

2.1. Systematic review and network meta‐analysis register

Our study has been registered with PROSPERO's International Prospective Register of Systematic Reviews under the registration ID: CRD42023387421.

2.2. Search strategy

A comprehensive search strategy was employed to retrieve relevant articles from various databases, including PubMed, Embase, Web of Science and others. The search was conducted from the inception of each respective database to November 2022. The search terms used were a combination of subject words and free‐text terms in English. These terms encompassed a range of variations related to stem cells, MSCs and diabetic wounds. The search strategy utilized Boolean operators to combine Medical Subject Headings (MeSH) terms and keywords. The following search terms were used:

Stem cell

Mesenchymal

Stem cells

Mesenchymal stem cell

Bone marrow mesenchymal stem cells

Bone marrow mesenchymal stem cell

Bone marrow stromal cell

Bone marrow stromal cells

Multipotent

Multipotent bone marrow stromal cell

Multipotent bone marrow stromal cells

Adipose‐derived mesenchymal stem cells

Adipose‐derived mesenchymal stromal cells

Mesenchymal stem cells

Adipose‐derived mesenchymal stem cells

Adipose‐derived mesenchymal stem cell

Adipose tissue‐derived mesenchymal stem cell

Adipose tissue‐derived mesenchymal stem cells

Adipose tissue‐derived mesenchymal stromal cells

Mesenchymal stromal cell

Stromal cell, mesenchymal

Stromal cells, mesenchymal

Multipotent mesenchymal stromal cells

Multipotent mesenchymal stromal cell

Mesenchymal stromal cells

Multipotent mesenchymal progenitor cell

Mesenchymal progenitor cells

Progenitor cell, mesenchymal

Progenitor cells, mesenchymal

Wharton jelly cells

Wharton's jelly cells

Wharton's jelly cell

Bone marrow stromal stem cells

Diabetic wound

Diabetic ulcer

Diabetic foot

Diabetic feet

This comprehensive search strategy was used to identify relevant studies in the specified databases for the research.

2.3. Inclusion and exclusion criteria

The inclusion criteria for this study were as follows:

Research subjects: Animal models of diabetic skin ulcers.

Intervention measures: Studies in which the treatment group utilized MSCs from various sources to treat diabetic wounds. The control group could employ physiological saline or other therapeutic interventions.

Research type: Only randomized controlled trials (RCTs) were considered for inclusion.

Outcome indicators: Studies must have assessed at least one of the following outcome indicators: wound healing rate, vascular density, epidermal thickness or any other relevant indicators related to wound healing in diabetic skin ulcers.

Studies meeting these specific inclusion criteria were considered for analysis in this research.

The exclusion criteria for this study were as follows:

Non‐diabetic ulcers: Studies that focused on non‐diabetic ulcers or wound healing in non‐diabetic contexts were excluded.

Irrelevant interventions: Studies that did not correspond to interventions involving MSCs for the treatment of diabetic wounds were excluded.

Lack of measurement data: Studies that did not provide measurement data related to the specified outcome indicators, such as wound healing rate, vascular density, epidermal thickness or other relevant wound healing parameters, were excluded.

Non‐English literature: Non‐English language studies were excluded from consideration.

Unavailable full text: Studies for which the full text was not accessible were also excluded from the analysis.

These exclusion criteria were applied to ensure that only relevant and high‐quality studies meeting the specified criteria were included in the research analysis.

2.4. Literature selection

The literature management and selection process involved several key steps as outlined below:

Import and duplicate removal: All retrieved literature was imported into Endnote software, and duplicate publications were meticulously eliminated.

Initial screening: Two independent researchers reviewed the titles and abstracts of the literature. During this stage, the literature was screened according to the predetermined inclusion and exclusion criteria to determine its initial potential for inclusion.

Full manuscript examination: Literature that passed the initial screening underwent a thorough examination of the full manuscripts to ascertain whether they met the inclusion criteria.

Resolution of disagreements: In the event of disagreements between the two researchers regarding the eligibility of a study, they engaged in discussion to reach a consensus. If consensus could not be reached, a third‐party arbitrator was consulted to make the final decision regarding the inclusion or exclusion of the literature.

Validity assessment and data extraction: Studies that were selected based on the inclusion criteria underwent a comprehensive validity assessment and data extraction process. This included collecting essential information such as publication date, first author, research topic, sample size, intervention measures, outcome indicators and other relevant data.

Recording excluded studies: Excluded studies, along with the reasons for their exclusion, were meticulously recorded. This documentation helps provide transparency regarding the selection process.

The systematic approach to literature management and selection ensures the integrity and reliability of the research findings by adhering to the predefined inclusion and exclusion criteria and addressing disagreements through discussion or third‐party arbitration.

The process of literature selection is shown in Figure 1.

FIGURE 1.

Study selection process.

2.5. Literature quality evaluation

The quality assessment of the included studies was conducted using the STAIR checklist, which consists of seven criteria. Each criterion was assigned a score as follows:

‘No’ = 0 points

‘Unclear’ = 1 point

‘Yes’ = 2 points

The overall quality of the articles was determined based on the total score achieved. The classification was as follows:

1–4 points: Low quality

5–8 points: Medium quality

9–12 points: High quality

This scoring system allows for a standardized evaluation of the quality of the included studies, with higher scores indicating higher quality research.

2.6. Data collection

Data were independently extracted by two reviewers with disagreements resolved by discussion with a third reviewer. The authors of the selected publications were contacted to clarify data or provide missing data when necessary.

The following data were extracted and recorded independently by the same two reviewers: (1) author, (2) year of publication, (3) MSCs origin, (4) control group, (5) outcome indicators, such as wound healing rate on days 7–8, wound healing rate on days 10–12, wound healing rate on days 12–14, vascular density, epidermal thickness, and so forth, using the mean value and standard deviation in the synthesis (6) animal model, (7) number of animals.

2.7. Statistical analysis

The R 4.2.2 software based on Bayesian analysis is used to draw the network evidence map and make the network meta‐analysis. The blue circles in the network evidence map represent MSCs from different sources, and the existence of connecting lines between the circles indicates that there is a direct comparison, and the thickness of the connecting lines represents the number of studies.

In this study, the Markov chain Monte Carlo (MCMC) model is used for simulation, with four Markov chains, 50 000 iterations, and annealing for the first 20 000 times, and the step size is 1. The potential scale reduction factor (PSRF) is used to evaluate the iterative convergence. If PSRF ≥1.1, it indicates that the current number of iterations is not enough to achieve good convergence, and the number of iterations needs to be increased. When PSRF <1.1, the closer to 1, it indicates that the model has good convergence. If there is a closed loop in the network evidence diagram, the difference between direct comparison and indirect comparison is calculated by the node‐splitting method, and the consistency is detected. If p ≥ 0.05, the difference is not statistically significant and the consistency is good. The odds ratio is used as the combined statistic for the second classification data, the standardized mean difference is used as the combined statistic for the continuous data and a 95% confidence interval is used for evaluation and comparison. The source of heterogeneity was found by subgroup analysis and sensitivity analysis, and only descriptive analysis was done when the source of heterogeneity could not be determined. Scatter plot asymmetry and statistical tests for publication bias were not performed.

3. RESULTS

3.1. Literature retrieval

After searching Embase, PubMed and Web of Science databases, a total of 1349 relevant papers were obtained, and 623 duplicates were found after duplicate checking. After reading the titles and abstracts of the literature, 663 irrelevant papers were excluded, 52 articles were excluded after reading the full text and finally, 11 papers were included for systematic review and network meta‐analysis. ²² , ²³ , ²⁴ , ²⁵ , ²⁶ , ²⁷ , ²⁸ , ²⁹ , ³⁰ , ³¹ , ³² The basic characteristics of the literature which were included can be viewed in Table 1. The relevant outcomes of each included study have been shown in Table 2.

TABLE 1.

Characteristics of trials included in this study and STAIR assessment.

Author	Year	Animal model	Sample size		Intervening measure		Stair
			Experimental group	Control group	Experimental group	Control group
Ding	2019	Female db/db mice	12	12	ADSCs	PBS	8
Chokesuwattanaskul	2018	Male BALB/C nude mice	12	12	BMMSCs	CPBS	10
Kim	2012	Male NOD/severe combined immuno‐deficiency mice	6	6	AMMs	ADSCs	8
Shi	2020	Specific pathogen‐free adult female Sprague–Dawley rats	15	15	UCMSCs	PBS	8
Shrestha	2013	Male db/db mice	6	6	UCMSCs	PBS	8
Yan	2017	Male ICR mice	6	6	BMMSCs	CM	7
Wan	2013	Male Wistar rats	12	12	BMMSCs	PBS	8
Huang	2021	Male C57BL/6J mice	15	15	UCMSCs	Untreated	8
Ahmed	2021	Rabbits	6	6	BMMSCs	Untreated	7
Meng	2014	OPN knock‐out mice	9	9	BMMSCs	Medium	8
SHIN	2012	Impaired healing BKS.Cg‐Dock7m+/+Leprdb/J (db/db) mice	10	10	BMMSCs	PBS	4

Abbreviations: ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

TABLE 2.

The relevant outcomes of each included study.

Author	Year	Outcome
Ding	2019	Wound healing rate on days 3, 7, 10 and 14 Histology and the retention of ADSCs in the wound tissue Wound vascularization
Chokesuwattanaskul	2018	Wound healing rate on days 7 and 14 Capillary density on days 7 and 14
Kim	2012	Wound healing rate on days 7, 10 and 14 Engraftment and differentiation rates
Shi	2020	Wound healing rate on days 3, 8 and 16 Histological assessment of ulceration healing
Shrestha	2013	Wound healing rate on days 0, 2, 4, 6, 10, 12 and 14 Capillary density
Yan	2017	Wound healing rate on days 7, 14 and 21 Quantitative evaluation on days 7, 14 and 21
Wan	2013	Wound healing rate on days 2, 5, 8 and 11 The thickness of granulation tissue Angiogenesis and cellular proliferation The content of VEGF
Huang	2021	Wound healing rate on day 12 Bacterial loads assessment Histological examination of skin wounds ELISA assay
Ahmed	2021	Wound healing rate on day 4, 8, 12 and 16 Period of epithelialization Collagen content estimation Histochemical analysis
Meng	2014	Wound healing time Wound healing rate on days 3, 5, 7, 14 and 21 Microvascular density
SHIN	2012	Wound healing rate on day 15

Abbreviations: ADSC, adipose‐derived mesenchymal stem cells; ELISA, enzyme‐linked immunosorbent assay; VEGF, vascular endothelial growth factor.

3.2. The basic characteristics of the incorporated literature

The basic characteristics of the included papers has been displayed in Table 1 and Table 2.

3.3. Network meta‐analysis results

3.3.1. Wound healing rate on days 7–8

Nine articles reported the effects of MSCs from fat, bone marrow, amniotic membrane and umbilical cord on promoting the healing rate of diabetic wounds on days 7–8. The net relationship between the healing rates of different MSCs has been shown in Figure 2. The results of the network meta‐analysis showed that there were no significant differences in efficacy among these MSCs (Table 3). According to the probability ranking chart, the effects of four kinds of MSCs on wound healing are from high to low: amniotic MSCs > adipose MSCs > umbilical cord MSCs > bone marrow MSCs (Table 4).

FIGURE 2.

Network diagram of wound healing rate on days 7–8. ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

TABLE 3.

Head‐to‐head comparisons of the efficacy of the mesenchymal stem cells from different sources on days 7–8.

	ADSCs	AMMs	BMMSCs	CM	CPBS	Medium	PBS	UCMSCs	Untreated
ADSCs	ADSCs	1.19 (0.89, 1.6)	0.74 (0.49, 1.13)	0.69 (0.41, 1.16)	0.59 (0.35, 0.99)	0.71 (0.43, 1.21)	0.68 (0.51, 0.92)	0.83 (0.58, 1.19)	0.58 (0.35, 0.97)
AMMs	0.84 (0.62, 1.13)	AMMs	0.62 (0.37, 1.04)	0.58 (0.32, 1.05)	0.49 (0.27, 0.9)	0.6 (0.33, 1.1)	0.58 (0.38, 0.88)	0.7 (0.44, 1.12)	0.48 (0.27, 0.88)
BMMSCs	1.35 (0.89, 2.06)	1.61 (0.96, 2.69)	BMMSCs	0.94 (0.7, 1.26)	0.79 (0.59, 1.07)	0.97 (0.72, 1.31)	0.93 (0.69, 1.25)	1.12 (0.78, 1.62)	0.78 (0.58, 1.05)
CM	1.45 (0.86, 2.42)	1.72 (0.95, 3.11)	1.07 (0.79, 1.44)	CM	0.85 (0.56, 1.3)	1.03 (0.68, 1.58)	0.99 (0.65, 1.51)	1.2 (0.75, 1.91)	0.83 (0.55, 1.27)
CPBS	1.7 (1.01, 2.84)	2.03 (1.11, 3.68)	1.26 (0.93, 1.69)	1.18 (0.77, 1.79)	CPBS	1.22 (0.8, 1.86)	1.17 (0.76, 1.77)	1.41 (0.88, 2.25)	0.98 (0.64, 1.5)
Medium	1.4 (0.83, 2.34)	1.67 (0.91, 3)	1.03 (0.77, 1.39)	0.97 (0.63, 1.47)	0.82 (0.54, 1.25)	Medium	0.96 (0.63, 1.46)	1.16 (0.72, 1.86)	0.81 (0.53, 1.23)
PBS	1.46 (1.08, 1.96)	1.74 (1.14, 2.63)	1.08 (0.8, 1.45)	1.01 (0.66, 1.53)	0.86 (0.56, 1.31)	1.04 (0.68, 1.6)	PBS	1.21 (0.98, 1.49)	0.84 (0.55, 1.28)
UCMSCs	1.21 (0.84, 1.74)	1.44 (0.9, 2.29)	0.89 (0.62, 1.28)	0.83 (0.52, 1.33)	0.71 (0.44, 1.14)	0.86 (0.54, 1.39)	0.83 (0.67, 1.02)	1.21 (0.98, 1.49)	0.7 (0.44, 1.11)
Untreated	1.74 (1.03, 2.89)	2.07 (1.14, 3.72)	1.28 (0.95, 1.72)	1.2 (0.79, 1.83)	1.02 (0.67, 1.56)	1.24 (0.81, 1.9)	1.19 (0.78, 1.8)	1.44 (0.9, 2.29)	Untreated

Abbreviations: ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

TABLE 4.

Rank probabilities for the efficacy of the mesenchymal stem cells from different sources on days 7–8.

	V1	V2	V3	V4	V5	V6	V7	V8	V9
ADSCs	1.04	2.36	1.05	1.02	1.01	1.01	1.01	1	1
AMMs	2.47	1.05	1.02	1.01	1.01	1.01	1	1	1
BMMSCs	1	1.01	1.05	1.83	1.24	1.09	1.03	1.01	1
CM	1.01	1.02	1.04	1.07	1.15	1.45	1.32	1.06	1.03
CPBS	1	1.01	1.01	1.01	1.02	1.03	1.07	1.65	1.42
Medium	1.02	1.02	1.05	1.15	1.55	1.18	1.12	1.04	1.02
PBS	1	1	1.01	1.08	1.12	1.31	1.55	1.06	1.03
UCMSCs	1.02	1.04	2.17	1.07	1.04	1.03	1.02	1.01	1.01
Untreated	1	1	1.01	1.01	1.02	1.03	1.05	1.37	1.74

Abbreviations: ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

3.3.2. Wound healing rate on days 10–12

Six articles reported the effects of MSCs from fat, bone marrow, amniotic membrane and umbilical cord on promoting the healing rate of diabetic wounds on days 10–12. The net relationship between the healing rates of different MSCs has been shown in Figure 3. The results of the network meta‐analysis showed that there were no significant differences in efficacy among these MSCs (Table 5). According to the probability ranking chart, the effects of four kinds of MSCs on wound healing are from high to low: amniotic MSCs > adipose MSCs > umbilical cord MSCs > bone marrow MSCs (Table 6).

FIGURE 3.

Network diagram of wound healing rate on days 10–12. ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

TABLE 5.

Head‐to‐head comparisons of the efficacy of the mesenchymal stem cells from different sources on days 10–12.

	ADSCs	AMMs	BMMSCs	PBS	UCMSCs	Untreated
ADSCs	ADSCs	1.15 (0.62, 2.14)	0.79 (0.34, 1.76)	0.67 (0.36, 1.24)	0.98 (0.43, 2.2)	0.63 (0.26, 1.5)
AMMs	0.87 (0.47, 1.61)	AMMs	0.68 (0.24, 1.88)	0.58 (0.24, 1.39)	0.85 (0.3, 2.35)	0.55 (0.19, 1.59)
BMMSCs	1.27 (0.57, 2.94)	1. 47 (0.53, 4.15)	BMMSCs	0.85 (0.5, 1.49)	1.25 (0.67, 2.34)	0.81 (0.47, 1.39)
PBS	1.5 (0.81, 2.78)	1.73 (0.72, 4.11)	1.18 (0.67, 1.99)	PBS	1. 47 (0.85, 2.49)	0.95 (0.5, 1.75)
UCMSCs	1.02 (0.45, 2.33)	1.73 (0.72, 4.11)	0.8 (0.43, 1.49)	0.68 (0.41, 17)	UCMSCs	0.65 (0.38, 1.1)
Untreated	1.58 (0.67, 3.82)	1.82 (0.63. 5.36)	1.24 (0.72. 2.12)	1.05 (0.57, 1.98)	1.55 (0.91, 2.65)	Untreated

Abbreviations: ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

TABLE 6.

Rank probabilities for the efficacy of the mesenchymal stem cells from different sources on days 10–12.

	V1	V2	V3	V4	V5	V6
ADSCs	1.14	1.53	1.28	1.11	1.06	1.03
AMMs	1.74	1.22	1.11	1.06	1.04	1.05
BMMSCs	1.05	1.11	1.18	1.5	1.22	1.07
PBS	1	1.01	1.06	1.23	1.47	1.39
UCMSCs	1.29	1.25	1.44	1.11	1.04	1.01
Untreated	1.01	1.03	1.06	1.12	1.31	1.68

Abbreviations: ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

3.3.3. Wound healing rate on days 12–15

Nine articles reported the effects of MSCs from fat, bone marrow, amniotic membrane and umbilical cord on promoting the healing rate of diabetic wounds on days 12–15. The net relationship between the healing rates of different MSCs has been shown in Figure 4. The results of the network meta‐analysis showed that there were no significant differences in efficacy among these MSCs (Table 7). According to the probability ranking chart, the effects of four kinds of MSCs on wound healing are from high to low: amniotic MSCs > umbilical cord MSCs > adipose MSCs > bone marrow MSCs (Table 8).

FIGURE 4.

Network diagram of wound healing rate on days 12–15. ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

TABLE 7.

Head‐to‐head comparisons of the efficacy of the mesenchymal stem cells from different sources on days 12–15.

	ADSCs	AMMs	BMMSCs	CPBS	Medium	PBS	UCMSCs	Untreated
ADSCs	ADSCs	1.14 (0.71, 1.82)	0.94 (0.51, 1.76)	0.89 (0.41, 1.96)	0.88 (0.43, 1.8)	0.67 (0.42, 1.08)	1.09 (0.58, 2.03)	0.73 (0.37, 1.43)
AMMs	0.88 (0.55, 1.42)	AMMs	0.83 (0.38, 1.82)	0.79 (0.31, 1.97)	0.78 (0.33, 1.84)	0.59 (0.3, 1.16)	0.96 (0.44, 2.1)	0.64 (0.28, 1.46)
BMMSCs	1.06 (0.57, 1.98)	1.21 (0.55, 2.66)	BMMSCs	0.95 (0.59, 1.52)	0.94 (0.67, 1.32)	0.71 (0.47, 1.07)	1.16 (0.72, 1.86)	0.78 (0.52, 1.18)
CPBS	1.12 (0.51, 2.44)	1.27 (0.51, 3.19)	1.05 (0.66, 1.69)	CPBS	0.99 (0.56, 1.77)	0.75 (0.4, 1.4)	1.21 (0.6, 2.37)	0.82 (0.44, 1.53)
Medium	1.13 (0.56, 2.3)	1.29 (0.54, 3.02)	1.06 (0.76, 1.49)	1.01 (0.57, 1.8)	Medium	0.76 (0.45, 1.29)	1.23 (0.69, 2.19)	0.83 (0.48, 1.4)
PBS	1.49 (0.93, 2.4)	1.7 (0.86, 3.31)	1.4 (0.93, 2.11)	1.33 (0.71. 2.49)	1.32 (0.78, 2.24)	PBS	1.62 (1.07, 2.44)	1.09 (0.68, 1.76)
UCMSCs	1.49 (0.93, 2.4)	1.05 (0.48, 2.29)	0.87 (0.54. 1.39)	0.82 (0.42, 1.61)	0.81 (0.46, 1.46)	0.62 (0.41, 0.93)	UCMSCs	0.67 (0.45, 1.01)
Untreated	1.37 (0.7, 2.67)	1.56 (0.68, 3.53)	1.29 (0.85, 1.93)	1.23 (0.65, 2.28)	1.21 (0.71, 2.06)	0.92 (0.57, 1.48)	1.49 (0.99, 2.24)	Untreated

Abbreviations: ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

TABLE 8.

Rank probabilities for the efficacy of the mesenchymal stem cells from different sources on days 12–15.

	V1	V2	V3	V4	V5	V6	V7	V8
ADSCs	1.06	1.28	1.34	1.13	1.12	1.11	1.05	1.02
AMMs	1.64	1.23	1.09	1.06	1.06	1.05	1.03	1.03
BMMSCs	1.03	1.1	1.2	1.45	1.26	1.07	1.01	1
CPBS	1.08	1.09	1.11	1.17	1.22	1.27	1.09	1.07
Medium	1.04	1.06	1.1	1.16	1.27	1.35	1.08	1.04
PBS	1	1	1.01	1.02	1.03	1.08	1.26	1.88
UCMSCs	1.36	1.33	1.24	1.09	1.06	1.04	1.01	1
Untreated	1	1.01	1.02	1.04	1.07	1.13	1.67	1.24

Abbreviations: ADSC, adipose‐derived mesenchymal stem cells; AMM, amniotic mesenchymal stem cell; BMMSC, bone marrow mesenchymal stem cell; UCMSC, umbilical cord mesenchymal stem cell.

4. DISCUSSION

4.1. Overview of the principles of MSC therapy for diabetic wounds

Presently, the therapeutic approach for diabetic cutaneous ulcers encompasses pressure alleviation, debridement, antibiotic‐based infection control and revascularization to reinstate blood circulation. ³³ , ³⁴ Nevertheless, these conventional treatment modalities primarily target wound closure without addressing the underlying wound pathophysiology. This limitation can lead to suboptimal healing, protracted recovery periods and recurrent wounds, ultimately culminating in treatment ineffectiveness. ³⁵

Stem cell‐based therapies offer a promising avenue for the treatment of diabetic skin ulcers. They possess the unique ability to address and circumvent the underlying aberrations in healing mechanisms and disrupted cell signalling present in diabetic wounds, thereby facilitating the healing process of diabetic skin ulcers. ³⁶ , ³⁷ Stem cells can be categorized into three main types: embryonic stem cells, pluripotent stem cells and somatic stem cells. MSCs, falling under the somatic stem cell category, exhibit remarkable attributes such as robust self‐renewal, the capacity for multilineage differentiation and immunomodulatory capabilities. MSCs can be sourced from various mature tissues, including bone marrow, adipose tissue, placenta, scalp, amniotic membrane, umbilical cord blood, among others. ³⁸ Regardless of their origin, MSCs from diverse sources function in a similar manner, expediting the healing process through two primary mechanisms. These mechanisms include the paracrine effect, where MSCs release signalling molecules to influence nearby cells, and direct differentiation into skin cells, such as fibroblasts and keratinocytes. ³⁹

MSCs exhibit the capacity to release an array of bioactive substances, comprising insulin‐like growth factor (IGF), hepatocyte growth factor (HGF), transforming growth factor β‐1 (TGF‐β1), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), fibroblast growth factor 2 (FGF2), platelet‐derived growth factor (PDGF), fibronectin, collagen I and others. ⁴⁰ These factors play pivotal roles across various stages of the wound healing process, encompassing the promotion of cell migration, proliferation and differentiation. While the precise mechanism governing the direct differentiation of MSCs into specific skin cell types remains not entirely elucidated, it has been observed that MSCs possess the capability to differentiate into diverse types of resident cells upon application to the wound site. The primary mechanism driving this differentiation of stem cells into endothelial cells, fibroblasts or keratinocytes is believed to be the local secretion of various bioactive substances. ⁴¹ In addition to these shared characteristics, it is noteworthy that various sources of MSCs may employ slightly different mechanisms to facilitate the healing of diabetic skin ulcers.

4.2. Specific mechanisms of different sources of MSCs for the treatment of diabetic wounds

Bone marrow mesenchymal stem cells (BMMSCs) stand out as one of the most frequently employed stem cell types in both clinical and preclinical investigations focused on diabetic skin ulcer treatment. ¹⁶ , ²⁰ Following the formation of diabetic skin ulcers, the biomechanical characteristics of the skin undergo disruption, resulting in diminished tensile strength due to the abnormal regulation of miR‐29a, consequently leading to a reduction in collagen content. This noteworthy issue has been addressed by researchers such as Carlos Zgheib and others who have observed that BMMSCs play a role in reducing miR‐29a levels. This action, in turn, leads to an increase in collagen levels, thereby ameliorating the compromised biomechanical properties associated with diabetic skin ulcers. ²² In a study investigating the potential link between the enhanced healing of diabetic skin ulcers through mesenchymal stromal cells and the metabolic alterations induced by their paracrine activity, a significant discovery emerged. Specifically, it was observed that IGF‐1, secreted by BMMSCs, upregulates GLUT4 expression within wounds via the PI3K/AKT pathway, independent of insulin. This phenomenon leads to accelerated metabolism and diminished insulin resistance throughout the diabetic skin ulcer healing process. ⁴² Impaired autophagy in epidermal cells stands as a significant impediment to the healing of diabetic skin ulcers. In a study conducted by Shi et al., ⁴³ it was revealed that hypoxic BMMSCs possess the capability to rejuvenate epidermal autophagy via the HIF‐1α/TGF‐β1/SMAD pathway. This restoration of autophagy plays a pivotal role in actively promoting the healing of diabetic wounds.

Adipose tissue has the advantage of yielding a higher quantity of MSCs in a shorter timeframe compared to bone marrow. This is due to the considerably greater concentration of adipose‐derived mesenchymal stem cells (ADSCs) per unit volume of tissue in comparison to bone marrow MSCs. ⁴⁴ Furthermore, liposuction, the method used for adipose tissue extraction, is less invasive than bone marrow aspiration, and ADSCs can be readily expanded on a large scale. ³⁶ Despite the pivotal role played by ADSCs in the healing of diabetic skin ulcers, their specific mechanism of action remains incompletely elucidated. ⁴⁵ Notably, in a study involving diabetic foot ulcer (DFU) rats, Li et al. demonstrated that ADSCs can expedite skin wound healing by fostering vascularization. ⁴⁶

The angiogenic attributes of ADSCs stem from their combined effect, involving direct participation in the formation of new blood vessels as well as their extensive paracrine activities that stimulate angiogenesis through the secretion of multiple molecules. ⁴⁴ Wei Zhang and fellow researchers have made noteworthy contributions to this field by highlighting the beneficial impact of ADSC‐Exos, which are naturally secreted nanoparticles derived from ADSCs, on the process of cutaneous wound healing. These nanoparticles expedite the proliferation and migration of fibroblasts, while also enhancing collagen synthesis. Notably, ADSC‐Exos may promote and optimize collagen synthesis by upregulating the PI3K/Akt signalling pathway during the cutaneous wound healing process. ⁴⁷ Furthermore, research has elucidated that ADSC‐CM (ADSC‐conditioned medium) effectively fosters lymphangiogenesis. ADSC‐CM has been shown to significantly enhance the proliferation, migration, tube formation, sprouting and invasiveness of human dermal lymphatic endothelial cells in vitro. ⁴⁸ ADSCs play a pivotal role in enhancing VEGFR3‐mediated lymphangiogenesis by means of METTL3‐mediated m6A modification of VEGF‐C, thereby contributing to the improvement of wound healing in diabetic skin ulcers. ⁴⁹ These intricate mechanisms hold fundamental importance in the context of tissue regeneration. ⁵⁰ However, it is noteworthy that diabetes can adversely impact the functionality of ADSCs and alter their intrinsic characteristics. As a consequence, this can impede their capacity to effectively promote wound healing in diabetic rats. ⁵¹

Umbilical cord mesenchymal stem cells (UCMSCs), owing to their origin, possess a degree of inherent protection from the external environment, allowing them to maintain their original characteristics. ⁵² Furthermore, due to their remarkable potential for multi‐lineage differentiation, they hold significant promise in the realms of non‐healing ulcer treatment and tissue regeneration. ⁵³ In a related study, Yanfu Han and colleagues highlighted the potential connection between impaired wound healing induced by diabetes and the accumulation of advanced glycosylation end products (AGEs). Their research revealed that transplantation of UCMSCs induces autophagy through the HIF‐1α/BNIP3/Beclin‐1 pathway and facilitates the removal of AGEs via autophagy/cathepsin processes. This dual mechanism has the potential to enhance diabetic wound healing, presenting novel insights and strategies for the treatment of diabetic skin ulcers. ²⁷ Additionally, human umbilical cord mesenchymal stem cells are known to secrete miRNAs that effectively mitigate excessive scar hyperplasia and contribute to enhanced wound healing. ⁵⁴ , ⁵⁵ , ⁵⁶

In recent years, amniotic mesenchymal stem cells (AMMs) have garnered significant attention as one of the most promising stem cell types within the realm of regenerative medicine. ⁵⁷ AMMs are derived from the superficial amniotic membrane of the placenta, endowing them with several advantageous characteristics. These include their ease of acquisition, convenience, abundant sources, robust proliferation capacity and notable differentiation potential. Importantly, the use of AMMs is associated with minimal ethical controversy. Research conducted by Li has demonstrated that AMMs possess the capability to inhibit apoptosis through the activation of the PI3K/AKT pathway, stimulate the proliferation of skin cells and accelerate the process of wound healing. ⁵⁷ Furthermore, experiments involving the direct transplantation of amniotic membrane loaded with AMMs into a mouse model with skin wounds have yielded promising results. These studies have shown that this approach promotes skin healing by facilitating the regeneration of epidermal stem cells and the formation of new capillaries. ²⁴ , ⁵⁸ , ⁵⁹ , ⁶⁰ Diverse microenvironments can prompt AMMs to differentiate into various tissue types and cell lineages. An important discovery by Francesco Alviano and colleagues revealed that, even in the absence of VEGF, certain AMMs underwent spontaneous differentiation into endothelial cells during the culture process. This differentiation became more pronounced when VEGF was introduced, underscoring the capability of AMMs for enhanced vascularization under appropriate conditions. ⁶¹ This observation strongly suggests that AMMs have the capacity to undergo effective vascularization following transplantation. ⁶² In a study that assessed the therapeutic potential of AMMs using a diabetic mouse wound model, Sung‐Whan Kim and colleagues made a significant finding. They observed that AMMs exhibit a notable capacity for differentiating into keratinocytes and display remarkable cell survival potential within wound sites. ²⁴ These studies collectively highlight the considerable value and promise of AMMs in the field of regenerative medicine.

4.3. The results of the network meta‐analysis of this paper and its analysis

This particular study revealed that AMMs, ADSCs, BMMSCs and UCMSCs all exhibited similar effectiveness in promoting the healing of diabetic skin ulcers, with no statistically significant differences observed. The authors attribute this outcome to the shared underlying principles among MSCs from different sources when it comes to enhancing the healing of diabetic ulcers. Almost all MSCs demonstrate anti‐inflammatory, microenvironmental improvement, pro‐angiogenic, anti‐fibrotic and anti‐apoptotic functions in the context of diabetic skin ulcer treatment. These functions are largely mediated through mechanisms such as the release of paracrine cytokines and their ability to differentiate into various skin cell lineages, including keratinocytes and endothelial cells, among others.Furthermore, it's important to note that the observation period for evaluating the effects of the treatments was relatively short, limited by the available studies. Consequently, the only outcome indicators that could be quantitatively analysed were the ulcer healing rates on days 7–8, 10–12 and 12–15. Although no statistical differences were found in these results, it's worth mentioning that, based on the ranking results from the network meta‐analysis, AMMs appear to exhibit the strongest potential in promoting the healing of diabetic skin ulcers among the four sources of MSCs evaluated. The ranking of the efficacy of different MSC sources in promoting diabetic wound healing was as follows: AMMs > ADSCs > UCMSCs > BMMSCs. The rationale behind this ranking is further analysed in conjunction with findings from other studies, as elaborated below.

AMMs exhibit a stronger amplification capacity compared to BMMSCs and they possess enhanced differentiation potential and plasticity. ⁶³ , ⁶⁴ In a study conducted by Sung‐Whan Kim and colleagues, it was observed that AMMs express significantly higher levels of representative proangiogenic genes such as VEGF‐A, angiopoietin‐1, HGF and FGF‐2 in comparison to ADSCs. ⁶⁵ These critical angiogenic genes, known for their beneficial effects on angiogenesis, are notably abundant in AMMs. The combined presence of these factors is believed to have a synergistic effect in promoting angiogenesis. Additionally, among the differentially up‐regulated genes, the expression of IGF‐1 in AMMs surpasses that in ADMS. ²⁴ IGF‐1 has been extensively validated for its pivotal role in cell survival and tissue regeneration across various tissues. ⁶⁶ , ⁶⁷ This study also made an important discovery regarding AMMs, noting their significant expression of Akt, a key player in cell survival mechanisms. ⁶⁸ It was observed that a greater number of successfully implanted AMMs survived in the ischemic hindlimb in vivo in comparison to ADSCs. These findings underscore the robust cell survival properties of AMMs, suggesting that they may yield more favourable therapeutic outcomes in ischemic conditions. ²⁴ , ⁶⁵ Furthermore, Bayesian network meta‐analysis studies have consistently demonstrated the superiority of amniotic membrane‐based therapies in promoting the healing of DFUs. ⁶⁹ , ⁷⁰ These findings align seamlessly with the results obtained in the present study.

While BMMSCs have traditionally served as the primary source of MSCs, a comparison of their biological properties with those of ADSCs has revealed a significant discrepancy. Specifically, it was noted that the number of ADSCs present in the same volume of adipose tissue exceeded that of BMMSCs in bone marrow tissue by over tenfold. ⁷¹ Moreover, accessing ADSCs involves simpler separation techniques. ⁷² Conversely, obtaining BMMSCs is associated with a high degree of invasiveness, rendering the widespread use of BMMSCs for the treatment of diabetic wounds impractical. Additionally, Li et al. have proposed that UCMSCs possess a greater amplification capacity and that their fundamental properties remain unaltered even after amplification. ⁷³ This disparity may be attributed to the presence of a substantial number of growth and development‐related cytokines in UCMSCs, which have the capacity to stimulate cell division and proliferation. ⁷⁴ These studies collectively suggest that, in terms of the biological characteristics of MSCs from various sources, ADSCs and UCMSCs may offer broader application prospects compared to BMMSCs. Furthermore, investigations into the ability of ADSCs and BMMSCs to differentiate into endothelial cells have been conducted and compared. The results indicated that both BMMSCs and ADSCs can induce differentiation into endothelial cells, although ADSCs tend to achieve this differentiation in a shorter timeframe. ⁷⁵ Aboulhoda and Abd El Fatta have compared the role of BMMSCs and ADSCs in full‐thickness cortical defects in rats, the result revealed that ADSCs have shown statistically significant improvement in inflammation, granulation tissue re‐organization and collagen deposition relative to their bone marrow‐treated counterparts. ⁷⁶ Wang Sqi and colleagues conducted a comparative study to assess the capacity of three types of MSCs—BMMSCs, ADSCs and UCMSCs—in promoting endothelial progenitor cells (EPCs) to form blood vessels and maintain vascular stability. The findings from this research indicate that ADSCs exhibit superior abilities compared to BMMSCs and UCMSCs in promoting EPCs to form functional blood vessels both in vitro and in vivo. ⁷⁷ Upon closer examination, it has been observed by some researchers that when co‐cultured with EPCs, ADSCs exhibit a higher secretion of angiogenic‐related cytokines compared to BMMSCs and UCMSCs. These cytokines include VEGF A, lipocalin, matrix metalloproteinase 9, interferon‐γ, complexin kinase receptor 2, chemokine, and others. It's worth noting that fibroblasts and keratinocytes, which are pivotal cells in the dermal and epidermal layers, play crucial roles in maintaining skin health and function. Fibroblasts play a crucial role in producing extracellular matrix components and essential proteins for maintaining skin structure. On the other hand, keratinocytes primarily serve to protect the body against potential damage from factors such as heat, pathogenic bacteria, viruses and other environmental threats. ⁷⁸ , ⁷⁹ , ⁸⁰ Research has shown that exosomes derived from ADSCs possess the strongest capability to induce fibroblast proliferation, while those from UCMSCs exhibit the weakest induction in this regard. However, when it comes to inducing keratinocyte proliferation, both ADSCs‐ and UCMSCs‐derived exosomes demonstrate similar and higher levels compared to exosomes from BMMSCs. ⁸¹ Additionally, by integrating data from in vitro studies with findings from in vivo and molecular mapping studies, Najmeh Kaffash Farkhad has concluded that UCMSCs display a greater angiogenic potential than BMMSCs. ⁸² , ⁸³ , ⁸⁴ , ⁸⁵ In vivo studies have also indicated that ADSCs exhibit a stronger capacity for promoting angiogenesis when compared to BMMSCs. ⁸⁶ , ⁸⁷ , ⁸⁸

The network meta‐analysis of wound healing rates at days 7–8 and 10–12 did not reveal significant differences among the various sources of MSCs. Based on the analysis of ranking probabilities, the order of effectiveness for MSC sources was determined as AMMs > ADSCs > UCMSCs > BMMSCs. Similarly, the data from the network meta‐analysis of wound healing rates on days 12–15 also demonstrated largely similar efficiency among MSCs from different sources, with the ranking probabilities indicating AMMs > UCMSCs > ADSCs > BMMSCs. These results can be attributed to the following factors.

Some studies have indicated that ADSCs exhibit more prominent adipogenesis compared to UCMSCs and respond better to neuronal induction methods, leading to a higher differentiation rate in a relatively shorter timeframe. ⁸⁹ , ⁹⁰ , ⁹¹ TNF‐α plays a pivotal role as a mediator of inflammation, capable of promoting the differentiation of MSCs into adipocytes and inducing senescence within an inflammatory microenvironment. ⁹² , ⁹³ The elevated expression of TNF‐α in ADSCs may account for the more efficient adipogenic differentiation observed in ADSCs compared to UCMSCs. ⁹¹ These underlying principles can elucidate why ADSCs outperform UCMSCs in the rankings for days 7–8 and 10–12. In general, cells derived from foetal sources tend to exhibit quicker proliferation rates and lower levels of senescence during extended culture when compared to MSCs derived from adult tissues. ⁹⁴ Furthermore, foetal‐derived MSCs are less susceptible to external influences such as environmental factors. ⁹⁵ In contrast, adult‐derived MSCs experience a decline in cell number, expansion capacity and differentiation potential as they age. ⁹⁶ , ⁹⁷ , ⁹⁸ Foetal‐derived MSCs, on the other hand, exhibit higher cell counts and superior proliferative capacity, enabling the rapid generation of large cell populations for clinical transplantation purposes. ⁹⁹ The presence of a placental barrier provides UCMSCs with a reduced risk of bacterial and viral infections compared to ADSCs, BMMSCs and others. ¹⁰⁰ The authors posit that these characteristics described above may account for the higher ranking of UCMSCs compared to ADSCs on days 12–15.

4.4. The limitations of this study

The small sample size in this study is a result of the limited number of available studies that met the inclusion criteria. Additionally, there is a considerable diversity in the presentation of outcome indicators beyond wound healing rates in the relevant literature, making it challenging to perform quantitative analyses on these parameters. Consequently, the conclusions drawn in this paper may necessitate further scrutiny through larger‐scale, high‐quality RCTs.

It's important to note that in the animal experiments included in this study, the ADSCs, AMMs and UCMSCs used for treatment were of human origin, while the majority of the BMMSCs were derived from animals, with only one case involving human‐derived BMMSCs. This discrepancy may be attributed to the technical complexity and invasiveness associated with obtaining BMMSCs from humans. Given the limited available literature, some of the animal experiments in this study employed human‐derived MSCs, while others utilized animal‐derived MSCs. This difference could potentially introduce bias into the results and should be considered as one of the key factors influencing the outcomes. While numerous studies have illustrated the capacity of MSCs to enhance the healing of diabetic skin ulcers, it's important to note that a majority of these studies have been conducted in animal models, with fewer carried out in human subjects.

The literature incorporated in this mesh meta‐analysis involves animal models encompassing various species such as mice, rats, rabbits and others. The diversity of animal models utilized in this study contributes to a broad representation, suggesting a certain degree of representativeness and accuracy in the obtained results. However, the heterogeneity and complexity inherent in human diabetic skin ulcers present challenges, as no single animal model can fully replicate every clinical scenario. ¹⁰¹ Furthermore, in the utilization of diabetic animal models, there exists variability in protocols across different laboratories, including differences in the age of animals and the type and size of wounds. This variability makes the comparison of datasets challenging. ¹⁰¹ Therefore, for the results of this mesh meta‐analysis to be applied clinically, further refinement of diabetic animal models through randomized controlled validation and clinical trials is necessary.

Consequently, further validation of their efficacy and safety in human clinical trials is necessary to establish their effectiveness definitively. ³⁶ , ⁴¹ When applying the findings of this paper, decision‐makers should take into account a range of factors to determine the most suitable MSC source for specific clinical situations. Future research should place emphasis on assessing both the therapeutic and economic advantages of utilizing various sources of MSCs, with the aim of enhancing the management of diabetic skin ulcers and facilitating their recovery.

5. CONCLUSION

Various sources of MSCs have exhibited substantial potential in the treatment of diabetic skin ulcers. The data derived from the network meta‐analysis presented in this paper suggests that there isn't a significant difference in the ability of different MSC sources to facilitate the healing of diabetic wounds. However, among these sources, AMMs may offer the most effective treatment for diabetic skin ulcers.

FUNDING INFORMATION

This work was supported by National Natural Science Foundation of China, Grant/Award Number: 81971842.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest, financial or otherwise.

Jin X, Yang L, Pan L, et al. Systematic review and network meta‐analysis of mesenchymal stem cells in treating diabetic skin ulcers in animal models. Int Wound J. 2024;21(2):e14663. doi: 10.1111/iwj.14663

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.