Methods and Limitations of Augmenting Mesenchymal Stem Cells for Therapeutic Applications

Huerta, Carlos Theodore; Ortiz, Yulexi Y.; Liu, Zhaojun; Velázquez, Omaida C.

doi:10.1089/wound.2022.0107

Cited by 14 publications

(17 citation statements)

References 113 publications

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“…This therapy could serve as an allogeneic cell therapy derived from young, healthy donors with MSCs modified ex vivo with a clinically safe vector, AAV/E-selectin, to be available as an off-the-shelf regenerative medicine product. Furthermore, the high transduction efficiency of this AAV-E-Selectin vector, preexisting clinical safety data on AAV vectors, and cost-effective scalability of AAV vectors for future clinical work make the use of this form of genetic manipulation more attractive than other vectors such as lentivirus or adenovirus and gene-editing platforms such as CRISPR/Cas9 systems 15,29 . Similar to unmodified and GFP-expressing MSCs, modifying MSCs in this manner did not appear to affect their normal functionality with regards to their proliferative ability or trilineage differentiation capacity.…”

Section: Discussionmentioning

confidence: 98%

“…Many genetic methods to alter MSCs can be associated with undesirable off-target effects on MSC populations by reducing their native self-renewal and differentiation properties 15,27 . We employed a clinically safe AAV vector to transfer the E-selectin gene into bone marrow–derived MSCs, which do not express E-selectin in normal conditions.…”

Section: Discussionmentioning

confidence: 99%

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Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs

Huerta

Ortiz

et al. 2023

Annals of Surgery

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Objective: Here, we report a new method to increase the therapeutic potential of mesenchymal stem/stromal cells (MSCs) for ischemic wound healing. We tested biological effects of MSCs modified with E-selectin, a cell adhesion molecule capable of inducing postnatal neovascularization, on a translational murine model. Background: Tissue loss significantly worsens the risk of extremity amputation for patients with chronic limb-threatening ischemia. MSC-based therapeutics hold major promise for wound healing and therapeutic angiogenesis, but unmodified MSCs demonstrate only modest benefits. Methods: Bone marrow cells harvested from FVB/ROSA26SormTmG donor mice were transduced with E-selectin-green fluorescent protein (GFP)/AAV-DJ or GFP/AAV-DJ (control). Ischemic wounds were created via a 4 mm punch biopsy in the ipsilateral limb after femoral artery ligation in recipient FVB mice and subsequently injected with phosphate-buffered saline or 1×106 donor MSCGFP or MSCE-selectin-GFP. Wound closure was monitored daily for 7 postoperative days, and tissues were harvested for molecular and histologic analysis and immunofluorescence. Whole-body DiI perfusion and confocal microscopy were utilized to evaluate wound angiogenesis. Results: Unmodified MSCs do not express E-selectin, and MSCE-selectin-GFP gain stronger MSC phenotype yet maintain trilineage differentiation and colony-forming capability. MSCE-selectin-GFP therapy accelerates wound healing compared with MSCGFP and phosphate-buffered saline treatment. Engrafted MSCE-selectin-GFP manifest stronger survival and viability in wounds at postoperative day 7. Ischemic wounds treated with MSCE-selectin-GFP exhibit more abundant collagen deposition and enhanced angiogenic response. Conclusions: We establish a novel method to potentiate regenerative and proangiogenic capability of MSCs by modification with E-selectin/adeno-associated virus. This innovative therapy carries the potential as a platform worthy of future clinical studies.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs

Huerta

Ortiz

et al. 2023

Annals of Surgery

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“…Local engraftment and survival of MSCs, especially in tissues with relative hypothermia and diminished blood supply, can be further improved through mechanical cell delivery systems and culture of aggregate 3D MSC spheroids. Combinations of these approaches may be elucidated in future studies to harness the maximum therapeutic effects of MSCs for clinical applications ( 78 ). Furthermore, future work should consider the ability of other cell-based therapies such as endothelial progenitor cells and mononuclear cells alone or in combination with MSCs for clinical revascularization strategies ( 47 ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: A review of preclinical and clinical studies

Huerta

Voza

Ortiz

et al. 2023

Front. Cardiovasc. Med.

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Progressive peripheral arterial disease (PAD) can result in chronic limb-threatening ischemia (CLTI) characterized by clinical complications including rest pain, gangrene and tissue loss. These complications can propagate even more precipitously in the setting of common concomitant diseases in patients with CLTI such as diabetes mellitus (DM). CLTI ulcers are cutaneous, non-healing wounds that persist due to the reduced perfusion and dysfunctional neovascularization associated with severe PAD. Existing therapies for CLTI are primarily limited to anatomic revascularization and medical management of contributing factors such as atherosclerosis and glycemic control. However, many patients fail these treatment strategies and are considered “no-option,” thereby requiring extremity amputation, particularly if non-healing wounds become infected or fulminant gangrene develops. Given the high economic burden imposed on patients, decreased quality of life, and poor survival of no-option CLTI patients, regenerative therapies aimed at neovascularization to improve wound healing and limb salvage hold significant promise. Cell-based therapy, specifically utilizing mesenchymal stem/stromal cells (MSCs), is one such regenerative strategy to stimulate therapeutic angiogenesis and tissue regeneration. Although previous reviews have focused primarily on revascularization outcomes after MSC treatments of CLTI with less attention given to their effects on wound healing, here we review advances in pre-clinical and clinical studies related to specific effects of MSC-based therapeutics upon ischemic non-healing wounds associated with CLTI.

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“…Cell transplantation therapies, including mesenchymal stem cell (MSC) transplantation, autologous cell transplantation, and direct chondrocyte transplantation, are effective modalities for treating growth plate injuries. − One of the most sought-after cell types for transplantation is MSCs, which are nonhematopoietic pluripotent stem cells with the ability to self-renew and differentiate into various mesenchymal cells, including osteogenic, chondrogenic, and adipogenic lineages. , However, uncontrolled chondrogenesis and the low survival rate of MSCs after transplantation pose significant challenges to their clinical application in cartilage regeneration . The conventional view is that chondrogenic differentiation of MSCs usually requires the induction of growth factors . Notwithstanding that growth factors, such as transforming growth factor-β (TGF-β), can promote chondrogenic differentiation of MSCs, they yield significant off-target effects on the cartilage matrix and lead to hypertrophy of MSCs .…”

Section: Introductionmentioning

confidence: 99%

“…10 The conventional view is that chondrogenic differentiation of MSCs usually requires the induction of growth factors. 11 Notwithstanding that growth factors, such as transforming growth factor-β (TGF-β), can promote chondrogenic differentiation of MSCs, they yield significant off-target effects on the cartilage matrix and lead to hypertrophy of MSCs. 12 Moreover, the guidance of MSC differentiation through cell signaling by these growth factors occurs in a dose-and timedependent manner, with unstable and uncertain outcomes.…”

Section: Introductionmentioning

confidence: 99%

Biodegradable Dual-Cross-Linked Hydrogels with Stem Cell Differentiation Regulatory Properties Promote Growth Plate Injury Repair via Controllable Three-Dimensional Mechanics and a Cartilage-like Extracellular Matrix

Guan

Kang

et al. 2023

ACS Appl. Mater. Interfaces

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Recent breakthroughs in cell transplantation therapy have revealed the promising potential of bone marrow mesenchymal stem cells (BMSCs) for promoting the regeneration of growth plate cartilage injury. However, the high apoptosis rate and the uncertainty of the differentiation direction of cells often lead to poor therapeutic effects. Cells are often grown under three-dimensional (3D) conditions in vivo, and the stiffness and components of the extracellular matrix (ECM) are important regulators of stem cell differentiation. To this end, a 3D cartilage-like ECM hydrogel with tunable mechanical properties was designed and synthesized mainly from gelatin methacrylate (GM) and oxidized chondroitin sulfate (OCS) via dynamic Schiff base bonding under UV. The effects of scaffold stiffness and composition on the survival and differentiation of BMSCs in vitro were investigated. A rat model of growth plate injury was developed to validate the effect of the GMOCS hydrogels encapsulated with BMSCs on the repair of growth plate injury. The results showed that 3D GMOCS hydrogels with an appropriate modulus significantly promoted chondrogenic differentiation of BMSCs, and GMOCS/ BMSC transplantation could effectively inhibit bone bridge formation and promote the repair of damaged growth plates. Accordingly, GMOCS/BMSC therapy can be engineered as a promising therapeutic candidate for growth plate injury.

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Methods and Limitations of Augmenting Mesenchymal Stem Cells for Therapeutic Applications

Cited by 14 publications

References 113 publications

Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs

Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs

Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: A review of preclinical and clinical studies

Biodegradable Dual-Cross-Linked Hydrogels with Stem Cell Differentiation Regulatory Properties Promote Growth Plate Injury Repair via Controllable Three-Dimensional Mechanics and a Cartilage-like Extracellular Matrix

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