A preview of selected articles

Severe blockages in arteries of the extremities can significantly reduce blood flow and prompt the onset of critical limb ischemia. The lack of circulation induces severe pain in the affected limbs (even when resting) and prompts the appearance of non‐healing sores and wounds that may lead to amputation of the affected limb if left untreated. Potential treatment approaches include promoting angiogenesis via the administration of angiogenic cytokines; however, stem cell‐based therapies have also garnered attention as a potentially effective means of promoting angiogenesis and tissue repair in critical limb ischemia patients. ¹ Approaches include administering mesenchymal stem cells (MSCs) from bone marrow or adipose tissue, with recent trials of bone marrow MSCs to promote angiogenesis and improve the functional activity of ischemic limbs/limb salvage provided evidence of safety and efficacy. ² , ³ Related research has suggested that the therapeutic function of MSCs derives from the secretion of anti‐inflammatory, immunomodulatory, and proangiogenic paracrine acting factors that support tissue repair and angiogenesis ⁴ , ⁵ ; therefore, many studies have attempted to delineate the specific mechanism by which MSCs contribute to ischemic tissue repair. In the first of our Featured Articles published this month in STEM CELLS Translational Medicine, Gupta et al report clinical data from the one‐year follow‐up of patients with critical limb ischemia receiving a pooled, allogeneic MSC product as part of a phase IV study. ⁶ In a Related Article published recently in STEM CELLS, Liu et al demonstrated that allogeneic MSCs improved ischemic muscle repair by recruiting and polarizing macrophages toward an M2 phenotype through a mechanism involving interleukin 10 (IL‐10) and hypoxia‐inducible factor‐1α (HIF‐1α). ⁷

Extracellular vesicles are a group of heterogeneous cell‐derived membranous structures comprising small‐sized vesicles (exosomes) originating from the endosomal compartment and middle‐sized vesicles (microvesicles) that bud from the cell membrane. ⁸ Extracellular vesicles are encountered in most, if not all, bodily fluids and play well‐described roles in cell‐to‐cell communication and tissue homeostasis ⁹ thanks to their bioactive cargos, which include proteins, lipids, DNA, and microRNAs. ¹⁰ Stem cell‐derived extracellular vesicles possess potent angiogenic, proliferative, and immunomodulatory abilities ¹¹ and may account for most of the paracrine therapeutic effect of stem cells (such as MSCs) post‐administration. ¹² , ¹³ For these reasons, treatments based on stem cell‐derived extracellular vesicles may represent a safe and efficient alternative to the administration of stem cells themselves. Current research aims in this field include attaining a better understanding of stem cell‐derived extracellular vesicle contents, how each individual component impacts target cells, and whether the tissue of origin influences the extracellular vesicle content and therapeutic potential. Meanwhile, related research has explored the therapeutic application of extracellular vesicles isolated from more readily available cell sources (such as fibroblasts) that suffer from fewer associated limitations. In the second of our Featured Articles published this month in STEM CELLS Translational Medicine, Gorgun et al characterize extracellular vesicles isolated from MSCs from the bone marrow and adipose tissue and demonstrate their differential therapeutic influence on endothelial proliferation and cartilage tissue maturation. ¹⁴ In a Related Article published recently in STEM CELLS, Oh et al provided evidence for the therapeutic capacity of extracellular vesicles isolated from murine fibroblast in a mouse model of full‐thickness wound healing. ¹⁵

FEATURED ARTICLES

Phase IV Study Confirms Safety and Efficacy of MSC Therapy for Critical Limb Ischemia

Previous research ¹⁶ from researchers led by Pawan Kumar Gupta (Stempeutics Research Pvt Ltd, Bangalore, India) reported the safe and effective application of stempeucel (a pooled, allogeneic MSC product isolated from the bone marrow of healthy adult volunteers) as an anti‐inflammatory, proregenerative, and proangiogenic treatment for critical limb ischemia in patients with Buerger's disease. This severe inflammatory disorder causes blood vessels to swell and prevents blood flow, which leads to clot formation and the need for limb amputation. ¹⁷ In their recent STEM CELLS Translational Medicine article, the authors report clinical data from a one‐year follow‐up of fifty patients as part of a phase IV study ⁶ ; encouragingly, they highlight the continuing safety, tolerability, and efficacy of stempeucel following intramuscular administration. Overall, fifty patients with “no‐option” critical limb ischemia received a stempeucel dose of two million cells per kilogram of body weight in the calf muscle and around ulcers. The study noted significant improvements in rest pain, ankle systolic pressure, and ankle brachial pressure index, increased healing rates of non‐healing ulcers, and decreased amputation rates at one‐year post‐administration. Furthermore, the authors failed to observe severe adverse effects associated with stempeucel administration, thereby suggesting the long‐term safety of their approach. Overall, these findings confirm the results of previous studies and suggest the continued long‐term safety, tolerability, and efficacy of stempeucel administration.

https://doi.org/10.1002/sctm.21-0197

Extracellular Vesicles from Different MSC Sources Differentially Impact Endothelial Proliferation and Chondrogenesis

MSCs exert much of their beneficial effects through the secretion of various paracrine‐acting factors, ¹⁸ which include extracellular vesicles (or EVs). As many studies have sought to compare and contrast MSCs from differing tissue sources with regards to their ability to induce specific effects or treat certain conditions, researchers from the laboratories of Roberta Tasso and Chiara Gentili (University of Genova, Italy) recently sought to identify functional differences between extracellular vesicles isolated from MSCs from the bone marrow and adipose tissue. Reporting in a recent STEM CELLS Translational Medicine article, Gorgun et al now establish the importance of selecting the appropriate cell source of extracellular vesicles for tissue‐specific therapeutic applications. ¹⁴ While both extracellular vesicular populations possessed similar characteristics in terms of size, concentration, and marker expression, they exhibited significant differences in protein content and functional effects. Extracellular vesicles from adipose MSCs contained a higher amount of proangiogenic factors (eg, GRO‐α, IL‐8, IGFBP3, and DKK‐1) and provoked a significantly greater increase in endothelial cord outgrowth than those isolated from bone marrow MSCs. Meanwhile, bone marrow MSC extracellular vesicles contained a higher level of factors that modulate angiogenic and osteogenic responses (eg, ANG‐2 and BDNF) and crosstalk with immune cells (eg, IFN‐γ, IL‐1α, and KLK‐3), which prompted an increase in the differentiation and maturation of cartilage tissue to a greater degree than extracellular vesicles isolated from adipose MSCs. Overall, these findings suggest that selecting an appropriate extracellular vesicle source represents an important factor when developing stem cell‐based therapeutic strategies.

https://doi.org/10.1002/sctm.21-0107

RELATED ARTICLES

Adipose MSCs Polarize Macrophages to Induce Critical Limb Ischemia Repair

Previous research from the laboratories of Xinwu Lu, Zhiyou Peng, and Kaichuang Ye (Shanghai JiaoTong University School of Medicine, Shanghai, China) underscored the considerable potential of allogeneic adipose MSC therapy as a means to repair/regenerate ischemic muscle. ¹⁹ , ²⁰ , ²¹ As we understand little regarding the molecular mechanisms involved, a recent STEM CELLS Translational Medicine article by Liu et al explored the potential for hypoxia‐activated MSCs to selectively polarize macrophages toward the alternatively activated anti‐inflammatory M2 phenotype. ⁷ Initial studies discovered that mouse macrophages displayed a reduced migratory capacity under the hypoxic conditions associated with ischemia. Interestingly, hypoxia decreased the differentiation propensity of MSCs but improved their paracrine output, which enhanced cocultured macrophage migration and polarized them into the anti‐inflammatory M2 phenotype. The crucial paracrine mechanisms mediating this process included the HIF‐1α mediated increase in IL‐10 secretion by MSCs, which subsequently activated the signal transducer and activator of transcription 3 (STAT3)/Arginase (Arg‐1) pathway. Moving in vivo, the authors confirmed that transplanted MSCs recruited macrophages to ischemic muscle and induced M2 polarization to support tissue regeneration. MSC transplantation into ischemic limbs significantly increased blood flow reperfusion and limb salvage rate, although tissue macrophage depletion or HIF‐1α‐silencing in MSCs inhibited these effects. The authors anticipated that their findings would foster the further development of allogeneic MSC therapies for ischemic limb repair and contribute to a deeper understanding of stem cell‐macrophage crosstalk.

https://doi.org/10.1002/stem.3250

Fibroblast Extracellular Vesicles Induce Full‐Thickness Wound Healing

Implementing MSC extracellular vesicles to accelerate and improve wound healing suffers from certain limitations (such as the time and cost associated with ex‐vivo expansion) ²² that have fostered the search for alternative, easier to attain cell sources. Researchers led by Ho Yun Chung and Byeong‐Cheol Ahn (Kyungpook National University Hospital, Daegu, South Korea) recently turned to skin fibroblasts, given their general abundance and closer associations with the skin and wound healing. ²³ In a recent STEM CELLS Translational Medicine article, Oh et al described the combination of murine fibroblast extracellular vesicles (L929‐EVs) and fibrin glue as a novel approach to inducing full‐thickness wound healing. ¹⁵ In vitro analysis first demonstrated that treatment with isolated and purified fibroblast extracellular vesicles led to increased fibroblast proliferation, migration, and wound healing‐associated gene expression (eg, MMP1, MMP3, and COL3A1); furthermore, fibroblast extracellular vesicles also improved endothelial cell migration and tube formation. Subsequent analysis after the in vivo administration of fibroblast extracellular vesicles in combination with fibrin glue (to aid retention within the wound) provided evidence for a greater degree of collagen formation, collagen maturation, angiogenesis, and hair follicle growth in a mouse full‐thickness wound healing model, suggesting a significant acceleration and improvement in scarless wound healing. While these findings supported the administration of fibroblast extracellular vesicles as a potentially effective wound healing strategy, the authors noted the need for further studies to describe those factors within extracellular vesicles with wound‐healing activity and define the therapeutic mechanisms induced in recipient cells.

https://doi.org/10.1002/stem.3310