Regenerative Medicine
18 results on this topic.
Research Papers
Reprogramming gut microenvironment for the treatment of acute severe ulcerative colitis via a synergistic therapy of necroptosis blockade and organoid transplantation.
Acute severe ulcerative colitis (ASUC) now imposes an increasing global burden, yet lacks broadly effective therapeutic options. While organoid transplantation represents a promising approach for intestinal injuries, its efficacy for ASUC treatment remains suboptimal. Here, we elucidate the intrinsic mechanism of RIPK1 involvement in necroptosis initiation, and further develop an organoid-based dual-axis therapeutic paradigm for ASUC. We identified that RIPK1 undergoes PIAS1-catalyzed SUMO1 modification at lysine 305, which promotes its compartmentalization within phase-separated structures, thereby serving as nucleation platforms for accelerating RIPK3 amyloid fibril assembly. Interfering with phase separation of RIPK1 suppresses necroptosis in intestinal cells and colonic organoids in vitro, as well as alleviates intestinal injury and reduces mortality in vivo. Notably, while colonic organoid transplantation showed limited therapeutic efficacy in ASUC, a synergistic therapy combining necroptosis blockade and organoid transplantation effectively reduced inflammatory damage and enhanced epithelial regeneration by reprogramming the intestinal microenvironment. These findings suggest that the SUMO1-RIPK1 axis functions as a druggable checkpoint governing necroptotic cell fate and presents a clinically actionable strategy to potentiate regenerative medicine paradigms in ASUC pathogenesis.
LNGFR promoting osteogenic differentiation of ectomesenchyme stem cells via activation of GHR-JAK-STAT/IGF1 signaling pathway.
Ectomesenchymal stem cells (EMSCs) are critical for craniofacial bone development, and low-affinity nerve growth factor receptor (LNGFR) is closely associated with their stemness. However, the specific role of LNGFR in EMSC osteogenesis remains unclear. Here, we investigated this using Lngfr knockout (lngfr-/-) mice and demonstrated that lngfr-/-EMSCs exhibited decreased proliferation, migration, and osteogenic differentiation capacities in vitro. Furthermore, impaired skeletal development and reduced mineralization were observed in lngfr-/- fetal mice in vivo. Circular RNA (circRNA) sequencing identified the growth hormone (GH) pathway as a key factor involved in LNGFR-regulated osteogenesis of EMSCs. Co-immunoprecipitation (Co-IP) assays further confirmed the interaction between LNGFR and growth hormone receptor (GHR). lngfr-/-suppressed GHR expression and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) phosphorylation, leading to downregulation of the GH/insulin-like growth factor 1 (IGF-1) signaling pathway. Modulation of the JAK/STAT pathway affected osteogenesis, while exogenous GH rescued the osteogenic defects via the GHR/JAK-STAT/IGF-1 axis. Collectively, these findings demonstrated that LNGFR promoted EMSC osteogenesis by activating the GHR/JAK-STAT/GH-IGF-1 signaling axis, providing new insights into craniofacial development and regenerative medicine.
Mesenchymal stromal cells therapy for remodeling the joint microenvironment: mechanisms, nanotechnology-enhanced strategies, and translation prospects.
Osteoarthritis (OA) is a complex, multifactorial whole-joint disease characterized by progressive articular cartilage degeneration, synovitis, and subchondral bone remodeling. Current clinical interventions primarily offer symptomatic management but do not halt or reverse disease progression. Recent advancements in regenerative medicine have emphasized mesenchymal stromal cell (MSC) therapy owing to its substantial potential in tissue repair and microenvironmental modulation. This review systematically evaluates the therapeutic efficacy and potential mechanisms of bone marrow-derived MSCs, adipose-derived stromal cells, umbilical cord-derived MSCs, synovium-derived MSCs, embryonic stem cell-derived MSCs and induced pluripotent stem cell-derived MSCs, as well as MSC-derived exosomes, in modulating the joint microenvironment. Furthermore, we discuss recent innovations in nanotechnology-enhanced strategies, designed to improve targeting specificity and therapeutic durability of MSC-based interventions. This review aims to establish a foundational framework and translational roadmap for the development of next-generation disease-modifying therapies for OA.
Randomized Double-Blind Placebo-Controlled Adaptive Design Trial Of Intrathecally Administered Autologous Mesenchymal Stem Cells In Multiple System Atrophy
Multiple system atrophy (MSA) is a rare, rapidly progressive, and invariably fatal neurological condition characterized by autonomic failure, parkinsonism, and/or ataxia. There is no available treatment to slow or halt disease progression. The purpose of this study is to assess optimal dosing frequency, effectiveness and safety of adipose-derived autologous mesenchymal stem cells delivered into the spinal fluid of patients with MSA. Funding source: FDA Office of Orphan Product Development (OOPD), Mayo Clinic Executive Dean for Research Transformational Award, Mayo Clinic Regenerative Medicine, and Mayo Clinic Department of Neurology. Phase: PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: Multiple System Atrophy Interventions: Autologous Mesenchymal Stem Cells; Placebo
Engineering tough blood clots for rapid haemostasis and enhanced regeneration.
Blood clots are pivotal for haemostasis and regeneration1, but they are mechanically weak and form slowly2, posing risks for life-threatening haemorrhage and limiting broader applications3-5. These limitations are attributed to complex coagulation cascades, abundant mechanically ineffective cells and little structural polymers. Strategies that strengthen polymer networks are inapplicable to these highly cellularized materials. Here we report a strategy that rapidly crosslinks red blood cells into tough cytogels and integrates them within blood clots. The resulting engineered blood clots (EBCs) form within seconds and exhibit a 13-fold increase in fracture toughness, and a 4-fold improvement in adhesion energy compared with native clots. Experiments and modelling identify the rupture of mechanically integrated cells as a key toughening mechanism. In vivo studies demonstrate that EBCs can rapidly halt haemorrhage, promote tissue regeneration, mitigate inflammation and foreign body reactions, and prevent postoperative adhesion. The safety and efficacy of both autologous and allogeneic EBCs were also validated. Our strategy is applicable to a range of cells and polymers. This work may motivate the development and translation of highly cellularized materials for bleeding control, wound management, tissue repair and regenerative medicine.
Phosphatidylserine-everted erythrocyte membrane vesicles enhance efferocytosis and remodeling of vascular grafts.
Erythrocytes and erythrocyte membrane vesicles have shown promise for personalized drug delivery through passive immune evasion, yet their active role in immune phagocytosis remains largely unexplored. Here, we introduce a paradigm based on phosphatidylserine-everted erythrocyte membrane vesicles that trigger efferocytosis, enabling immune-mediated tissue regeneration rather than immune evasion. Incorporation of these phosphatidylserine-everted erythrocyte membrane vesicles into small-diameter vascular grafts markedly enhances endothelialization, suppresses calcification, and improves long-term patency in a rabbit carotid artery replacement model. Preclinical evaluation in a large canine model further demonstrates superior performance compared with clinically used expanded polytetrafluoroethylene grafts. This study establishes engineered phosphatidylserine-everted erythrocyte membrane vesicles as a versatile, customizable, and cost-effective biointerface for vascular grafts and other blood-contacting devices, providing a compelling strategy to harness innate immune mechanisms for regenerative medicine.
A Prospective Comparative Study of Autologous Bone Marrow-Derived and Adipose Tissue-Derived Mesenchymal Stem Cells Versus Platelet-Rich Plasma and Standard Therapy in Patients With Organic Erectile Dysfunction
Erectile dysfunction (ED) is a common condition characterized by the inability to achieve or maintain an erection sufficient for satisfactory sexual activity. It can significantly affect physical health, emotional well-being, and quality of life for both patients and their partners. Standard treatment options include medications such as phosphodiesterase type 5 inhibitors, vacuum devices, intracavernosal or transurethral therapies, and surgical implantation of penile prostheses. In recent years, low-intensity shock wave therapy has also been introduced as a treatment option. However, these approaches may have limitations in effectiveness, invasiveness, or long-term outcomes, highlighting the need for alternative therapies. Advances in regenerative medicine have introduced new potential treatment strategies, including the use of autologous mesenchymal stem cells derived from bone marrow or adipose tissue. These therapies aim to improve tissue repair and restore erectile function. Previous preclinical and clinical studies suggest that mesenchymal stem cell therapy may be safe and effective, but direct comparisons between different sources of stem cells remain limited. This prospective study aims to evaluate and compare the safety and effectiveness of autologous bone marrow-derived mesenchymal stem cells, adipose tissue-derived mesenchymal stromal cells, and platelet-rich plasma (PRP) therapy in patients with organic erectile dysfunction. A control group receiving standard conservative treatment, including low-intensity shock wave therapy, will also be included. The study will be conducted in a population of patients in Kazakhstan and will assess outcomes before and after treatment to determine improvements in erectile function and overall patient well-being. The results may help identify more effective and regenerative treatment approaches for patients with organic erectile dysfunction. Phase: PHASE2 Status: ACTIVE_NOT_RECRUITING Conditions: Erectile Dysfunction Interventions: Autologous Bone marrow-derived Mesenchymal Stem Cells (BMSC); Autologous Platelet-Rich Plasma (4 mL); Autologous Platelet-Rich Plasma (6 mL); Adipose Tissue Mesenchymal Stromal Cells (ADSC); Low-intensity radial shock wave therapy (Li-SWT)
Rejuvenation of mesenchymal stromal cells via partial reprogramming enables scalable generation of transcriptionally diverse MSC libraries.
Mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but their clinical utility is limited by replicative senescence. Strategies that reverse aging while maintaining MSC identity are urgently needed.
Intrinsic mechanisms and microenvironmental cues fine-tune plasticity of esophageal progenitors.
Cell plasticity supports tissue regeneration but can also drive metaplasia, increasing cancer risk in many tissues, including the esophagus. Understanding how esophageal progenitor plasticity is regulated is therefore essential. We previously identified Sox9 as a key regulator of this plasticity downstream of Hedgehog signaling, which is reactivated by chronic acid reflux. Here, we show that Hedgehog regulates Sox9 indirectly through epithelial-stromal communication and directly via cell-autonomous mechanisms. Activation of TGF-β and BMP pathways synergistically induces Sox9 and promotes a transcriptomic state resembling squamo-columnar junction progenitors predisposed to metaplasia. We also uncover an epithelial cell-intrinsic mechanism whereby Cox-2 modulates this plasticity. Cox-2 inhibitors suppress Hedgehog-induced Sox9 expression through direct effects on epithelial cells in both mouse and human models. Together, these findings provide proof of concept that pharmacological modulation of epithelial plasticity may offer new strategies for regenerative medicine and for the prevention or treatment of metaplasia.
Transplantation of encapsulated mitochondria alleviates dysfunction in mitochondrial and Parkinson's disease models.
Mitochondrial transplantation holds significant potential for the treatment of mitochondrial diseases. However, how to efficiently deliver exogenous mitochondria to somatic cells or tissues remains unresolved. We present a mitochondrial transplantation approach to deliver mitochondria into the cells and tissues of mice and monkeys with high efficiency, based on encapsulating mitochondria with vesicles derived from the plasma membrane of erythrocytes. Treatment with encapsulated mitochondria complemented the loss, deletion, or mutation of mitochondrial DNA, thereby rescuing the associated bioenergetic and biochemical defects in patient-derived cells with mitochondrial disorders. Furthermore, mitochondrial capsules rescued the mitochondrial DNA depletion syndrome and Leigh syndrome in Dguok-/- and Ndufs4-/- mouse models, respectively. Moreover, in a mouse model of Parkinson's disease, mitochondrial capsules rescued neuron loss, improved motor skills, and restored mitochondrial function in the affected brain regions. Our study demonstrates the potential of this mitochondrial capsule as a treatment for mitochondrial disorders and proposes an "organelle therapy" strategy in regenerative medicine.
Mesenchymal Stem Cell and Exosome Therapy for Diabetic Erectile Dysfunction
The goal of this prospective randomized controlled clinical study is to evaluate the effectiveness and safety of intracavernosal injections of umbilical cord-derived mesenchymal stem cells (MSCs) and umbilical cord-derived MSC-derived exosomes in men aged 25 to 75 years with diabetic erectile dysfunction (ED) who have not responded adequately to conventional medical treatments such as phosphodiesterase type-5 (PDE-5) inhibitors. Diabetes mellitus is a major risk factor for erectile dysfunction and is associated with endothelial dysfunction, impaired smooth muscle relaxation, neuropathy, and increased fibrosis within penile tissue. Although many patients respond to standard pharmacological treatments, diabetic patients often demonstrate reduced responsiveness to these therapies. Regenerative medicine approaches, including stem cell therapy and stem cell-derived exosomes, have emerged as potential therapeutic strategies due to their regenerative, angiogenic, neuroprotective, and anti-fibrotic effects. The main questions this study aims to answer are: * Whether intracavernosal administration of mesenchymal stem cells or MSC-derived exosomes improves erectile function, as measured by changes in the International Index of Erectile Function-5 (IIEF-5) and Erectile Hardness Score (EHS). * Whether penile hemodynamics improve following treatment, as assessed by penile Doppler ultrasonography parameters including peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index (RI). Participants will be randomly assigned to one of three groups: * Intracavernosal placebo injection * Intracavernosal injection of umbilical cord-derived mesenchymal stem cells (5×10⁶ cells) * Intracavernosal injection of umbilical cord-derived mesenchymal stem cell-derived exosomes (75 μg) All interventions will be administered as a single intracavernosal injection under controlled clinical conditions. Participants will undergo baseline evaluation including medical history, physical examination, erectile function assessment using the IIEF-5 questionnaire, and penile Doppler ultrasonography. Follow-up evaluations will be conducted at 1, 3, 6, and 12 months after treatment to assess changes in erectile function, penile vascular parameters, and treatment-related adverse events. The study will also monitor potential side effects such as pain, bruising, hematoma, edema, or other complications related to the intracavernosal injection procedure. Participants will be recruited from patients presenting to the urology outpatient clinic with diabetic erectile dysfunction. Eligible participants must have a diagnosis of erectile dysfunction for at least six months, a history of diabetes mellitus for at least five years, and insufficient response to standard medical therapy. Patients with penile anatomical deformities, active infections, malignancy, unstable cardiovascular disease, autoimmune disease, or other contraindications to intracavernosal treatment will be excluded. Phase: PHASE2, PHASE3 Status: RECRUITING Conditions: Erectile Dysfunction With Diabetes Mellitus Interventions: Umbilical Cord-Derived Mesenchymal Stem Cells; Umblical Cord-Derived Mesenchymal Stem Cell-Derived Exosomes; Placebo Intracavernosal Injection
Intervertebral disc progenitor cells: roles in regeneration and disease.
Intervertebral disc (IVD) degenerative disease is a prevalent and debilitating spinal disease. Current treatments only focus on symptomatic relief but fail to halt disease progression or restore the native biomechanical function of the spine. Regenerative medicine strategies, particularly those harnessing endogenous progenitor cells, offer a promising avenue for achieving biological repair and functional homeostasis. The identification of intervertebral disc progenitor cells (IVD-PCs) has unveiled a potential cellular reservoir for self-repair, given their demonstrated stemness attributes, including clonogenicity and multipotent differentiation. However, the clinical translation of IVD-PCs is significantly hampered by an incomplete understanding of their inherent heterogeneity, hierarchical organization, and, most critically, the dynamic interplay with their unique microenvironment, which dictates their fate decisions. This review synthesizes recent advances in deciphering the molecular signatures and functional plasticity of IVD-PCs. We place a particular emphasis on how key physicochemical, mechanical, and cellular cues within the IVD niche orchestrate progenitor cell behavior-ranging from maintenance and activation to aberrant differentiation-during both homeostasis and degeneration. Furthermore, we propose forward-looking insights to bridge critical knowledge gaps, aiming to propel the development of novel progenitor cell-based therapeutics for IVD degeneration.
New legal category of 'advanced regenerative medicine treatment' in Korea's amended regenerative medicine law: comparative lessons from Japan.
South Korea's Act on the Safety of and Support for Advanced Regenerative Medicine and Advanced Biological Products, enacted in 2019, was recently amended. This article examines the new advanced regenerative medicine treatment (ARMT) category, focusing on patient access, review processes, safety monitoring, ethical safeguards, and lessons from Japan's comparable framework.
Pretreated mesenchymal stromal cells and their secretome for kidney disease: mechanisms and applications.
The issue of kidney disease represents a significant global health challenge. While current treatment options may provide symptomatic relief, they are limited by several factors. Consequently, there is a pressing need to create more effective therapeutic strategies. Mesenchymal stromal cell (MSCs) and their secretome have attracted considerable attention in the field of regenerative medicine owing to their multidirectional differentiation potential, immunomodulatory properties, and paracrine effects, which offer a promising solution to this challenge. However, direct transplantation of MSCs and their secretome faces problems such as low survival rate and unstable therapeutic effect in practical applications. These challenges have prompted researchers to explore strategies to enhance the therapeutic potential of MSCs and their secretory factors through pretreatment. This review summarizes the current research progress on pretreated MSCs and their secretome in the treatment of kidney diseases and discusses how various pretreatment approaches can enhance their therapeutic efficacy and clinical application in renal disorders, thereby providing insights for the future optimization and therapeutic use of MSCs.
Two decades of induced pluripotent stem cell research: From discovery to diverse applications.
Twenty years have passed since the first demonstration of mouse induced pluripotent stem cells (iPSCs). What began as an unexpected observation in Kyoto quickly transformed stem cell biology and regenerative medicine worldwide. Over the past two decades, we have gained profound insights into the molecular mechanisms underlying cellular reprogramming and pluripotency. The technology has continued to evolve-becoming safer, more efficient, and more versatile. Today, iPSCs serve as a foundation for wide-ranging applications, from disease modeling and drug discovery to regenerative therapies and rejuvenation research. In this review, I reflect on the scientific journey of iPSCs, highlight key milestones in our understanding of reprogramming, and discuss the expanding clinical and societal impact of iPSCs.
Safety and feasibility of intravenous fresh adipose-derived mesenchymal stem cells in secondary progressive multiple sclerosis: phase I/IIa clinical results.
Mesenchymal stem cells (MSCs) hold substantial promise in regenerative medicine owing to their immunomodulatory, neuroregenerative, and self-renewal properties. Adipose tissue (AT) serves as an optimal MSC source due to its high yield and rapid proliferation. This study evaluated the safety and exploratory clinical effects of non-cryopreserved, culture-expanded autologous AT-MSCs in patients with secondary progressive multiple sclerosis (SPMS).
Intrinsic and niche-dependent metabolic regulation of haematopoietic stem cells and implications for leukaemogenesis.
Haematopoietic stem cells (HSCs) rely on precisely coordinated metabolic programs to preserve their functionality, adapt to environmental cues, and sustain lifelong haematopoiesis. Here we analyse recent advances in understanding the metabolic landscape of HSCs, emphasizing how their intrinsic bioenergetic programs facilitate quiescence, self-renewal and differentiation. We also summarize the dynamic metabolic interactions with the bone marrow microenvironment, including stromal cells, osteoblasts, endosteal cells and adipose tissue, highlighting how they support proper HSC fate. In addition, we discuss how alterations in metabolic homeostasis in healthy and aged HSCs are linked to haematological disorders, particularly leukaemogenesis. We discuss metabolic dysregulation in leukaemic cells that maintains malignant persistence by mimicking certain intrinsic-extrinsic key HSC metabolic features, while simultaneously activating distinct metabolic pathways to support their growth and survival. Understanding the complex role of metabolism in HSC biology will be essential to advance regenerative medicine and blood cancer prevention strategies.
Generating high-quality porcine iPSCs with the new medium cocktail LACID.
Pigs are important for disease model generation, xenotransplantation, and interspecies organogenesis. Porcine induced pluripotent stem cells (piPSCs) should enable these efforts, but have not been generated to meet the attributes, such as feeder-free culture, robust development potential, and blastocyst generation through nuclear transfer. We report an improved strategy to generate such piPSCs. We show that chemically defined medium 3 promotes the formation of epithelium-like colonies in porcine reprogramming, which allows further reprogramming under the new medium cocktail LACID. The resulting piPSCs have key features, including flat morphology with feeder-free culture, generating robust teratoma and blastoids, forming chimeric blastocysts, and readily edited with CRISPR-Cas9. Lastly, nuclear transfer with piPSCs can develop into blastocysts. Despite maintaining a primed pluripotent state, our results suggest that the newly established LACID piPSCs may be ideal for applications in regenerative medicine. This method may be further improved to generate naive or totipotent stem cells.