Table 3.
Combinational strategies with stem cells enhancing angiogenesis and wound healing in DFUs: Exendin-4 (Ex-4) is a glucagon-like peptide-1 receptor agonist known to have many beneficial effects on diabetes, human adipose tissue-derive stem cells (hADSCs), long noncoding RNA (Lnc), bone marrow mesenchymal stem cells (BMSCs), self-assembled nano-peptide hydrogels with human umbilical cord mesenchymal stem cell spheroids (hUC-MSCsp), acellular dermal matrix (ADM), extra cellular matrix (ECM), hBM-MSCs/T/H/S embedded in an ECM scaffold (S) and preconditioned with hypoxia (H) and the β-adrenergic receptor antagonist, timolol (T), Wharton’s jelly mesenchymal stem cell (WJMSC), sodium ascorbyl phosphate (SAP), platelet rich plasma (PRP), human umbilical cord mesenchymal stem cells (hUC-MSCs), 5-aminolevulinic acid photodynamic therapy (ALA-PDT), EVs secreted by human umbilical cord mesenchymal stem cells (hucMSC-EVs), HOTAIR-MSC EVs- extracellular vesicles (EVs) isolated from mesenchymal stem/stromal cells (MSCs) transfected to overexpress long non-coding RNA HOX transcript antisense RNA (HOTAIR), endothelial cells (ECs), catechol-functionalized hyaluronic acid (HA-CA) patch.
| Treatment | Combination/Strategy | Assessing Parameters | Study Outcome |
|---|---|---|---|
| Exosomes from linc00511-overexpressing ADSCs [46] |
hADSCs-derived exosomes were injected into Sprague–Dawley (SD) rats along with human blood-derived EPC | Angiogenesis and wound healing Underlying molecular mechanism |
Accelerate angiogenesis and wound healing by suppressing PAQR3-induced Twist1degradation |
| BMSC-derived exosomal lncRNA KLF3-AS1 [47] | Exosomes were delivered via tail vein injection in diabetic BALB/C mice | Wound healing Angiogenesis |
Induction of angiogenesis to promote diabetic cutaneous wound healing. |
| Exosomes from pioglitazone pretreated MSCs [48] | Exosomes isolated from supernatants of pioglitazone-treated BMSCs (PGZ-Ex) were injected around the wounds by multisite subcutaneous injection | Wound healing Angiogenesis |
PGZ-EX accelerates diabetic wound healing via enhanced angiogenesis, increased collagen deposition, ECM remodeling, and increased VEGF and CD31 expression |
| hucMSC-EVs [49] | hucMSC-EVs applied locally to diabetic mice |
Angiogenesis Wound healing |
hucMSC-EVs have regenerative and protective effects on high glucose-induced endothelial cells involving the transfer of miR-17-5p to target PTEN/AKT/HIF-1α/VEGF pathway hucMSC-EVs promote angiogenesis and accelerate wound healing |
| HOTAIR-MSC EVs [50] | HOTAIR-MSC EVs were injected around the wound in Sprague–Dawley rats | Wound healing Angiogenesis |
HOTAIR-MSC EVs promote angiogenesis and wound healing in diabetic (db/db) mice. |
| Exendin-4 with ADSCs [51] | hADSCs were injected intradermally around the wound in db/db mice and Ex-4 was applied topically | Wound size Wound histology Angiogenesis |
The combination of topical treatment of Ex-4 and injection of ADSCs has a better effect therapeutically than Ex-4 alone |
| hUC-MSCsp [52] | hUC-MSCsp transplanted into wounded skin of mice model of diabetes | Wound healing Angiogenesis Inflammation Comparison between stem cells alone and in combination |
Accelerated wound healing Inhibited inflammation Promotes angiogenesis |
| ADSCs [53] | ADSCs in the acellular dermal matrix under hypoxic and normoxic conditions applied over DFU in a diabetic rat | Stem cell viability under hypoxic and normoxic conditions | The transplanted cells in the hypoxic-ADSCs/ADM membrane can survive longer at the chronic ulcer site and enhance angiogenesis, inhibits inflammation, and increase ECM formation |
| hBM-MSCs [54] | hBM-MSCs/T/H/S administered to porcine wound model | Wound healing Angiogenesis |
MSC/T/H/S promoted wound re-epithelialization and angiogenesis and improved wound healing |
| WJMSC [55] | WJMSC with PF-127 hydrogel and SAP were transplanted onto excisional cutaneous wound bed in type II diabetic Sprague–Dawley rats | Wound healing Mitochondrial damage and oxidative stress |
Promoted diabetic wound healing Decreased M1 and increased M2 macrophages Increased angiogenesis |
| ADSCs [56] | ADSCs (isolated from rats) alone and ADSCs with PRP was injected at the wound base and edges of diabetic Albino rats | To compare the efficacy of ADSC alone vs. ADSC+ PRP in wound healing and angiogenesis | PRP+ADSCs compared to their individual use are better for re-epithelialization, granulation tissue formation, collagen deposition, epidermal thickness, and angiogenesis by modulating the Notch pathway |
| ADSCs [57] | ADSCs (isolated from rats) combined with PRP were injected to wound in Sprague–Dawley rats | Angiogenesis Wound healing |
ADSCs-PRP induced a higher wound closure rate Increases the expression of VEGF, p-STAT3, and SDF-1 Promote ECs proliferation thereby neovascularization |
| hUC-MSCs [58] | hUC-MSCs combined with ALA-PDT- hUC-MSCs were injected intradermally to diabetic C57BL/6J mice after exposing the mice to ALA-PDT with 10% ALA gel and 25 J/cm2 of PDT. | To investigate the efficacy of the combinational approach on wound closure, angiogenesis, and inflammation | Combining ALA-PDT with hUC-MSCs possesses a significantly enhanced therapeutic efficacy in enhancing wound healing, promoting angiogenesis, and attenuating inflammation and bacterial load suggesting its efficacy in healing refractory wounds. |
| ADSCs [59] | ADSCs combined with HA-CA ADSCs were injected around the wound in diabetic C57BL/6 mice and a patch was deposited on the wound |
Angiogenesis Wound healing |
HA-CA + ADSCs enhanced wound healing and angiogenesis synergistically involving PI3K/AKT pathway. |
| ADSCs [60] | Human ADSCs with SDF-1α gene-activated scaffold were tested in vitro using HUVEC | Pro-angiogenic properties | SDF-1α gene-activated scaffold overcomes the deficiencies associated with diabetic ADSCs and restores pro-angiogenic features ln ADSCs |