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One of the attractive features of exosomes is that they are small and can travel between cells and deliver bioactive products, including miRNA, mRNA, proteins, and various other factors, to promote bone regeneration, with undetectable immune rejection. In this chapter, we intend to briefly update the recent progressions, and discuss the potential challenges in the target areas. Hopefully, our discussion would be helpful not only for the clinicians and the researchers in the specific disciplines but also for the general audiences as well.

Introduction

Osteogenesis and Bone Regeneration. Fractures are common traumatic injuries during the entire human history. Both traditional and modern medicine have kept on exploring and researching on many potential treatments. Surgical intervention with autologous bone graft seems to be the preferred method for such complication, but the secondary trauma and the limited resources of grafting bone make this approach still unsatisfactory [ 2 , 3 ].

Other methods, including active substance injection and bone marrow transplantation, are also used clinically but they face their own challenges, including the effectiveness, safety and immune rejection [ 4 , 5 ].

Therefore, how to promote fracture healing efficiently and safely is still the major focus of recent research in regenerative medicine for bone. Normal bone regeneration is a complex but well-orchestrated physiological process that includes the initiation of ossification, osteoinduction, and osteogenesis [ 6 , 7 , 8 , 9 ]. Within this microenvironment, abundant blood vessels accelerate the metabolism while bringing a large number of multipotential stem cells [ 11 , 12 ].

On the other hand, the mononuclear phagocyte system from the blood differentiates into osteoclasts in the newly established microenvironment, and the bone resorption, in turn, specifically stimulates the bone re-modeling process [ 13 , 14 ]. During the stereotyped osteogenesis process, stem cells proliferate and differentiate into osteoblasts and migrate to areas of bone defects and bone resorption, secreting collagen matrices [ 7 , 15 , 16 , 17 ], and then immature osteoblasts produce bone matrix containing calcium and phosphate to promote mineralization [ 18 ].

Of note, new blood vessels in the fracture microenvironment can also bring essential nutrients and mineral salt for fracture healing, improving the efficiency of osteogenic differentiation and bone regeneration [ 19 ]. Embryonic stem cell transplantation was considered as a potential promising treatment for tissue repair; however, due to the limitation of donor cells and biosafety issues, its clinical application has not been widely accepted [ 20 , 21 , 22 , 23 ].

Recently, it has been recognized that adult bone marrow-derived mesenchymal stem cells BMSCs might be a better alternative, and moreover, researchers found that BMSCs play an important role in promoting tissue regeneration through paracrine signaling [ 24 , 25 ], in addition to directly differentiation into bony tissue. This paracrine effect, mediated by signaling molecules, transcription factors, and other proteins, regulates a series of signaling pathways involved in bone regeneration. Further study found, that in addition to stem cells, many other cells, such as osteoblasts, can also produce exosomes [ 28 ].

Promoting the translation of basic research to the clinic

The key unanswered question is: could these different cell-derived exosomes promote bone regeneration and accelerate fracture healing? This chapter will focus on this important question. In , Harding found a lysosomal-like vesicle in reticulocytes of rats. It was found that transferrin was internalized by this vesicle and its receptors also recycled back to the plasma membrane through endocytosis [ 29 ].

It is now accepted that the extracellular vesicles secreted by cells could be generally classified as microvesicles, apoptotic bodies, and exosomes, on the basis of the size, cellular origin, content, and biological function [ 31 , 32 ].

The convergence of regenerative medicine and rehabilitation: federal perspectives

Currently, the exosomes are extensively studied. The formation of exosome is essentially the encapsulation of bioactive substances, including proteins and nucleic acids, into multivesicular bodies with the help of endosomal sorting complex in the cells [ 35 , 36 ]. The newly formed exosomes inside the cell are transported and fused with the plasma membrane and eventually released into the extracellular matrix [ 37 , 38 ].

Electron-microscopic observation of whole-mounted exosomes purified from mouse dendritic cells. Arrows indicate exosomes, arrowheads point to smaller nonexosomal vesicles.

It is now known that numerous different type of cells, including dendritic cells, mast cells, lymphocytes, neurons, and endothelial cells secrete exosomes [ 39 , 40 , 41 , 42 , 43 ], which are found in blood, amniotic fluid, urine, malignant ascites, and other body fluids such as bile [ 44 , 45 , 46 , 47 ]. The key features of exosomes as intercellular communicators is due to the fact that they are able to selectively carry the contents of the parent cells and act on target cells [ 31 , 38 ].


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In , Valadi found that exosomes contain RNA, which indicated exosomes might regulate genetic information flow [ 48 ]. In recent years, many studies have found that a variety of cell-derived exosomes contain mRNA and miRNA and play an important role in cell-to-cell signaling [ 48 , 49 , 50 ].

Therefore, the transport of RNA and active proteins through exosomes provides a novel pathway for activating target cell and initiating and propagating downstream signaling pathways. For example, in , Cantaluppi discovered that microvesicles from epithelial progenitor-derived cell initiated renal-regeneration procedures by carrying miRNAs and acting on target cells, reversing focal ischemic lesions [ 51 ]. The regenerative effects of exosomes have been validated in other tissues and organs, including the heart, lungs, kidneys, and brain [ 52 , 53 , 54 ].

For example, in a mouse model of myocardial infarction, treatment of exosomes can improve cardiac epicardial remodeling and increase left ventricular ejection fraction [ 55 ]. In hypoxic-induced pulmonary hypertension, exosome treatment inhibits disease progression and protects the lungs from hypertension [ 56 ]. In addition, exosome treatment can improve renal function in a mouse model of acute kidney injury [ 57 ].

These studies indicate that exosomes have the capacity to promote tissue regeneration, which provides a basis for their potential application in bone regeneration [ 58 ]. The mechanism of stem cells in the treatment of diseases has not been fully elucidated; however, it is now commonly accepted that there are two recognized mechanisms: differentiation and paracrine. In fact, it is becoming clearer that paracrine mechanism could be a more important mechanism; therefore, exosomes, as important mediators in paracrine mechanism, have attracted researchers.

Embryonic stem cells are considered to be the ideal materials for regenerative medicine because of their ability of pluripotent differentiation.

Therapeutic Use of Stem Cells and Regenerative Medicine

But later study found that bone marrow mesenchymal stem cell BMSC could be a better alternative, i. Similarly, the adipose-derived stem cells ADSCs can also be osteogenic differentiated to promote bone regeneration, when they have been applied to the bone defects using a composite biological scaffold [ 60 ]. In addition, endothelial progenitor cells EPCs can differentiate into vascular endothelial cells to generate blood vessels, and promote MSCs osteogenesis in a specific microenvironment [ 61 , 62 ].

Also, differentiated cells, such as osteoblasts and osteoclasts, also have the ability to promote bone regeneration [ 15 , 26 ]. More importantly, numerous studies suggest that the above-mentioned cell-derived exosomes all have a certain ability to promote bone regeneration, through regulating bone regeneration procedures such as angiogenesis, osteogenic differentiation, and bone mineral deposition.

However, the capacities and regeneration mechanisms of exosomes from different derived cells are somewhat inconsistent, likely due to their different contents. The statement includes five key principles, including a common commitment against germline genome modification unless and until ethical and potential safety questions with respect to germline gene editing are adequately addressed.

Thirteen developers have signed on to the statement.

Promises and Challenges of Stem Cell Research for Regenerative Medicine

Learn About Regenerative Medicine Regenerative medicine includes gene therapies, cell therapies, and tissue-engineered products intended to augment, repair, replace, or regenerate organs, tissues, cells, genes, and metabolic processes in the body. Discover the Alliance ARM takes the lead on the most important issues facing the regenerative medicine and advanced therapy sector today: Advocating for clear, predictable and harmonized regulatory and review pathways Enabling market access and value-based reimbursement policies Addressing industrialization and manufacturing hurdles Conducting key stakeholder outreach, communication and education Facilitating sustainable access to capital and identify sources of potential public funding.

Find Out More. To move regenerative medicine into the realms of mainstream medicine, better science and better regulation must be integrated with both innovative manufacturing methods that make treatments affordable, and a way to show how they ultimately benefit the patient and society as a whole. MNT is the registered trade mark of Healthline Media. Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a healthcare professional. Privacy Terms Ad policy Careers. Visit www.

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Heart failure could be treated using umbilical cord stem cells.

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