Muscle stem cell therapy for volumetric muscle loss

肌肉干细胞疗法治疗体积性肌肉损失

• 批准号: 10284923
• 负责人: Ngan F. Huang
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284923
• 关键词: Activities of Daily Living; Acute; Aftercare; Anatomy; Animals; Architecture; Biomechanics; Biomedical Engineering; Cell Transplantation; Cells; Chronic; Cicatrix; Clinical; Clinical Trials; Data; Degenerative Disorder; Endothelial Cells; Engineering; Engraftment; Excision; Exercise; Exercise Test; Fibroblasts; Foundations; Gastrocnemius Muscle; Generations; Goals; Health; Hematopoietic; Hindlimb; Histologic; Human; Hydrogels; Impairment; Implant; Individual; Injury; Lesion; Life; Minor; Mission; Modeling; Mus; Muscle; Muscle Fibers; Muscle function; Muscle satellite cell; Myoblasts; Natural regeneration; Neuromuscular Junction; Operative Surgical Procedures; Pattern; Physical activity; Physiological; Population; Property; Quality of life; Recovery; Recovery of Function; Regenerative Medicine; Regenerative capacity; Regenerative response; Rehabilitation therapy; Rodent Model; Running; Skeletal Muscle; Skeletal muscle injury; Skin; Skin graft; Stem cell transplant; Structure; Supporting Cell; Surgical Flaps; System; Technology; Testing; Therapeutic; Tissues; Translating; Transplantation; Trauma; Traumatic injury; Veterans; Work; base; design; disability; exercise regimen; functional outcomes; functional restoration; human stem cells; improved; in vivo; injured; muscle regeneration; muscle transplantation; nerve supply; novel therapeutic intervention; progenitor; regeneration potential; relating to nervous system; repaired; response; restoration; satellite cell; scaffold; scale up; standard of care; stem cell biology; stem cell function; stem cell niche; stem cell therapy; stem cells; technology development; therapeutically effective; tibialis anterior muscle; tissue repair; translation to humans; transplantation therapy; treadmill; treatment duration; vasculogenesis; volumetric muscle loss; wound closure

Major trauma can cause volumetric muscle loss (VML) resulting in life-long disability. Although skeletal muscle is capable of remarkable regenerative potential, when injury is massive and destroys the underlying architecture, regeneration is aborted and is characterized instead by scar tissue formation. The standard of care in such injuries is wound closure, leaving little hope for functional recovery. The promise of regenerative medicine is the full regeneration of damaged tissues, either by promoting repair from endogenous stem cells or by the transplantation of cells to enhance regeneration. Perhaps the best example of this is skin grafting in the setting of massive tissue loss in burn victims. The fact that grafted skin contains endogenous stem cells assures that the graft will not only restore function acutely but also chronically as the stem cells function to replenish skin cells that are lost during the normal turnover of the tissue. Likewise, the long-term goal of regenerative medicine is to be able to restore damaged tissue and maintain that tissue for the full lifetime of the individual. Major advances have been made in the culture and transplantation of muscle stem cells (MuSCs, also known as “satellite cells”) in recent decades, primarily in rodent models of muscle injury and degenerative disease. It has been known for over 40 years that transplanted myoblasts, the more differentiated progeny of MuSCs, can contribute to new muscle formation in the host. However, it has long been recognized that those cells have limited regenerative capacity and fail to form new stem cells. In our ongoing studies, supported by extensive Preliminary Data, we have been able to generate “bioconstructs” that consist of decellularized muscle scaffolds into which we have engrafted MuSCs in a hydrogel. When this whole bioconstruct is transplanted into a VML lesion in a mouse hindlimb muscle, we are currently able to achieve limited structural and functional restoration. The major focus of the studies of this proposal is the development of this technology so as to optimize MuSC treatment of VML lesions and to design a scalable therapy that could be translated to humans. Toward this goal, we have outlined three Specific Aims, each based on extensive Preliminary Data: 1) To enhance MuSC therapy by generative bioconstructs that contain other cellular components of the MuSC niche so as to improve the engraftment and de novo muscle fiber formation by the MuSCs; 2) To optimize the use of physical activity in the form of voluntary running or forced treadmill running to enhance the efficacy of MuSC treatment of VML lesions; and 3) To assess our ability to scale up our model using at 10-fold increase in VML size and treatment with two separate approaches – a direct scaling of our bioconstruct and the use of “modular” bioconstructs. The overall goal of this proposal is to develop a scalable technology using MuSC bioconstruct transplantation for the treatment of VML. This will have direct and immediate relevance to Veterans who are suffering from skeletal muscle injuries, injuries that have limited their functional capacity and that, to date, have had no hope of further recovery. Our goal is to develop a novel therapeutic approach to muscle tissue repair based upon a deep understanding of the basic stem cell biology, a state-of-the-art application of bioengineering approaches to these clinical challenges, and a firm commitment to the clinical/translational mission to improve the health and quality of life of Veterans whose function and further rehabilitation is limited by the lack of effective therapeutic options.

严重创伤可导致体积性肌肉损失（VML），导致终身残疾。尽管骨骼