Articles on Regenerative Medicine & Stem Cells

Our staff editors continue to share brilliant, thoughtful, and meaningful topics and articles in the recommended series.

This week, we would like to share several latest articles on Regenerative Medicine & Stem Cells.

Title: Therapeutic strategies of three-dimensional stem cell spheroids and organoids for tissue repair and regeneration
Authors: Woochan Kim, Yonghyun Gwon, Sunho Park, Hyoseong Kim, Jangho Kim
Type: Review Article
Highlights:
●Timeline and historical evolution of stem cell culture systems were reviewed.
●Engineering techniques for formation of stem cell spheroids and organoids were reviewed.
●Advanced therapeutic strategies of stem cells-based spheroids and organoids for tissue repair and regeneration were reviewed.
●Perspective on stem cells-based 3D therapeutic strategies were proposed.
Abstract:
Three-dimensional (3D) stem cell culture systems have attracted considerable attention as a way to better mimic the complex interactions between individual cells and the extracellular matrix (ECM) that occur in vivo. Moreover, 3D cell culture systems have unique properties that help guide specific functions, growth, and processes of stem cells (e.g., embryogenesis, morphogenesis, and organogenesis). Thus, 3D stem cell culture systems that mimic in vivo environments enable basic research about various tissues and organs. In this review, we focus on the advanced therapeutic applications of stem cell-based 3D culture systems generated using different engineering techniques. Specifically, we summarize the historical advancements of 3D cell culture systems and discuss the therapeutic applications of stem cell-based spheroids and organoids, including engineering techniques for tissue repair and regeneration.
Access this article: https://doi.org/10.1016/j.bioactmat.2022.03.039

Title: Non-electric bioelectrical analog strategy by a biophysical-driven nano-micro spatial anisotropic scaffold for regulating stem cell niche and tissue regeneration in a neuronal therapy
Authors: Xiangyun Yao, Lei Zhan, Zhiwen Yan, Juehong Li, Lingchi Kong, Xu Wang, Huimin Xiao, Huiquan Jiang, Chen Huang, Yuanming Ouyang, Yun Qian, Cunyi Fan
Type: Research Article
Highlights:
●Anisotropic rGO/PCL scaffolds had synergistic effect on ADSC neural differentiation.
●Transplanted GFP-ADSCs were extracted by FACS purification for RNA-sequencing.
●Bioelectric nerve niche reprogramed ADSC phenotypes via PI3K-AKT signaling.
●ADSC-loaded scaffolds efficiently repaired 15 mm sciatic nerve defect in rats.
Abstract:
The slow regenerating rate and misdirected axonal growth are primary concerns that disturb the curative outcome of peripheral nerve repair. Biophysical intervention through nerve scaffolds can provide efficient, tunable and sustainable guidance for nerve regrowth. Herein, we fabricate the reduced graphene oxide (rGO)/polycaprolactone (PCL) scaffold characterized with anisotropic microfibers and oriented nanogrooves by electrospinning technique. Adipose-derived stem cells (ADSCs) are seeded on the scaffolds in vitro and the viability, neural differentiation efficiency and neurotrophic potential are investigated. RGO/PCL conduits reprogram the phenotype of seeded cells and efficiently repair 15 mm sciatic nerve defect in rats. In summary, biophysical cues on nerve scaffolds are key determinants to stem cell phenotype, and ADSC-seeded rGO/PCL oriented scaffolds are promising, controllable and sustainable approaches to enable peripheral nerve regeneration.
Access this article: https://doi.org/10.1016/j.bioactmat.2022.05.034

Title: A reactive oxygen species-responsive hydrogel encapsulated with bone marrow derived stem cells promotes repair and regeneration of spinal cord injury
Authors: Ziming Li, Tengfei Zhao, Jie Ding, Haochen Gu, Qiaoxuan Wang, Deteng Zhang, Changyou Gao
Type: Research Article
Highlights:
●A ROS-scavenging hydrogel protects the encapsulated BMSCs in an inflammatory environment and attenuates inflammation.
●A ROS-scavenging hydrogel significantly reduces oxidative damage and inflammation in spinal cord injury.
●A BMSCs-encapsulated ROS-scavenging hydrogel promotes axon regeneration in vivo.
Abstract:
Spinal cord injury (SCI) is an overwhelming and incurable disabling event accompanied by complicated inflammation-related pathological processes, such as excessive reactive oxygen species (ROS) produced by the infiltrated inflammatory immune cells and released to the extracellular microenvironment, leading to the widespread apoptosis of the neuron cells, glial and oligodendroctyes. In this study, a thioketal-containing and ROS-scavenging hydrogel was prepared for encapsulation of the bone marrow derived mesenchymal stem cells (BMSCs), which promoted the neurogenesis and axon regeneration by scavenging the overproduced ROS and re-building a regenerative microenvironment. The hydrogel could effectively encapsulate BMSCs, and played a remarkable neuroprotective role in vivo by reducing the production of endogenous ROS, attenuating ROS-mediated oxidative damage and downregulating the inflammatory cytokines such as interleukin-1 beta (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), resulting in a reduced cell apoptosis in the spinal cord tissue. The BMSCs-encapsulated ROS-scavenging hydrogel also reduced the scar formation, and improved the neurogenesis of the spinal cord tissue, and thus distinctly enhanced the motor functional recovery of SCI rats. Our work provides a combinational strategy against ROS-mediated oxidative stress, with potential applications not only in SCI, but also in other central nervous system diseases with similar pathological conditions.
Access this article: https://doi.org/10.1016/j.bioactmat.2022.04.029

Title: A bioactive material with dual integrin-targeting ligands regulates specific endogenous cell adhesion and promotes vascularized bone regeneration in adult and fetal bone defects
Authors: Dake Hao, Ruiwu Liu, Tomas Gonzalez Fernandez, Christopher Pivetti, Jordan Elizabeth Jackson, Edwin Samuel Kulubya, Hong-Jiang Jiang, Hai-Yang Ju, Wen-Liang Liu, Alyssa Panitch, Kit S. Lam, J. Kent Leach, Diana L. Farmer, Aijun Wang
Type: Research Article
Highlights:
●Two integrin-binding ligands for constructing vascularized bone biomaterial.
●Extracellular matrix (ECM)-mimicking collagen-based biomaterial with specific integrin binding sites for cell adhesion.
●Biomaterial regulates adhesion of endogenous stem cells with osteogenic and angiogenic potentials.
●Biomaterial promotes vascularized bone formation in adult and fetal bone defects without safety issues.
●An easy-to-make and off-the-shelf biomaterial for treatment of clinical bone diseases.
Abstract:
Significant progress has been made in designing bone materials capable of directing endogenous cells to promote vascularized bone regeneration. However, current strategies lack regulation of the specific endogenous cell populations for vascularized bone regeneration, thus leading to adverse tissue formation and decreased regenerative efficiency. Here, we engineered a biomaterial to regulate endogenous cell adhesion and promote vascularized bone regeneration. The biomaterial works by presenting two synthetic ligands, LLP2A and LXW7, explicitly targeting integrins α4β1 and αvβ3, respectively, expressed on the surfaces of the cells related to bone formation and vascularization, such as mesenchymal stem cells (MSCs), osteoblasts, endothelial progenitor cells (EPCs), and endothelial cells (ECs). In vitro, the LLP2A/LXW7 modified biomaterial improved the adhesion of MSCs, osteoblasts, EPCs, and ECs via integrin α4β1 and αvβ3, respectively. In an adult rat calvarial bone defect model, the LLP2A/LXW7 modified biomaterial enhanced bone formation and vascularization by synergistically regulating endogenous cells with osteogenic and angiogenic potentials, such as DLX5+ cells, osteocalcin+ cells, CD34+/CD45- cells and CD31+ cells. In a fetal sheep spinal bone defect model, the LLP2A/LXW7 modified biomaterial augmented bone formation and vascularization without any adverse effects. This innovative biomaterial offers an off-the-shelf, easy-to-use, and biologically safe product suitable for vascularized bone regeneration in both fetal and adult disease environments.
Access this article: https://doi.org/10.1016/j.bioactmat.2022.05.027

Title: Extracellular magnetic labeling of biomimetic hydrogel-induced human mesenchymal stem cell spheroids with ferumoxytol for MRI tracking
Authors: Sen Yan, Miao Zhang, Jingyi Sheng, Xueqin Xu, Shijia Tang, Yan Li, Sheng Yang, Guangxiang Si, Yu Mao, Yi Zhang, Feimin Zhang, Ning Gu
Type: Research Article
Highlights:
●An extracellular magnetic labeling method was developed for MSC spheroids using ferumoxytol.
●Ferumoxytol encapsulated into abundant ECM proteins network of MSC spheroids ensured this method is stable and durable.
●Uniformly sized magnetic spheroids induced by mechanically tunable biomimetic hydrogels promoted MSCs stemness properties.
●Magnetically labeled MSC spheroids exhibited superior MRI imaging both in vitro and in vivo.
Abstract:
Labeling of mesenchymal stem cells (MSCs) with superparamagnetic iron oxide nanoparticles (SPIONs) has emerged as a potential method for magnetic resonance imaging (MRI) tracking of transplanted cells in tissue repair studies and clinical trials. Labeling of MSCs using clinically approved SPIONs (ferumoxytol) requires the use of transfection reagents or magnetic field, which largely limits their clinical application. To overcome this obstacle, we established a novel and highly effective method for magnetic labeling of MSC spheroids using ferumoxytol. Unlike conventional methods, ferumoxytol labeling was done in the formation of a mechanically tunable biomimetic hydrogel-induced MSC spheroids. Moreover, the labeled MSC spheroids exhibited strong MRI T2 signals and good biosafety. Strikingly, the encapsulated ferumoxytol was localized in the extracellular matrix (ECM) of the spheroids instead of the cytoplasm, minimizing the cytotoxicity of ferumoxytol and maintaining the viability and stemness properties of biomimetic hydrogel-induced MSC spheroids. This demonstrates the potential of this method for post-transplantation MRI tracking in the clinic.
Access this article: https://doi.org/10.1016/j.bioactmat.2022.04.024