Frontiers in Stem Cell and Regenerative Medicine Research: Volume 11 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Wissenschaft und neue Technologien
- Serie: Frontiers in Stem Cell and Regenerative Medicine Research
- Sprache: Englisch
Stem cell and regenerative medicine research is an important area of clinical research which promises to change the face of medicine as it will be practiced in the years to come. Challenges in the 21st century to combat diseases such as cancer, Alzheimer’s disease and retinal disorders, among others, may well be addressed employing stem cell therapies and tissue regeneration techniques. Frontiers in Stem Cell and Regenerative Medicine Research brings updates on multidisciplinary topics relevant to stem cell research and their application in regenerative medicine. The series is essential reading for researchers seeking updates in stem cell therapeutics and regenerative medicine.
Volume 11 includes 5 chapters on these topics:
- The use of embryology in clinical practice
- Molecular regulation and signaling transduction in human tissue development
- Cell differentiation on hydrogels and its application in regenerative medicine
- Stem cell therapy for sepsis
- Tumorigenicity assessments for stem cell-derived therapeutic products
Readership
Pharmaceutical scientists, biomedical researchers, stem cell biologists, pre-clinical and clinical researchers, life science, researchers, healthcare professionals in regenerative medicine
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Seitenzahl: 216
Veröffentlichungsjahr: 2024
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PREFACE
Stem cells and regenerative medicines have enormous potential for tissue engineering, multipotency, and self-renewal ability to address future challenges. The eleventh volume of ‘Frontiers in Stem Cell and Regenerative Medicine Research’ is another continuous effort to further strengthen this understanding of stem cells to show how quickly and successfully they are coming up with regenerative medicine. This field is developing leaps and bounds to a real translation into clinical practice. We welcome you to read this volume, wheres reviews are written by specialists in the key areas of stem cells and regenerative medicine, and discover more about the subject.
Remarkable studies on the beneficial effect of embryology to facilitate the understanding and application of this branch of science have widely captured the interest of scientists and physicians and encouraged students to embrace this discipline. Boroujeni et al. discussed recent data from several clinical trials and case reports on basic embryology with clinical practice including diagnosis and management of congenital defects and management of other diseases with the help of a developmental approach. Clinical applications and research horizons have also been discussed therein.
Another interesting report from Ahmadi et al., discussed the details of gene expression regulation, cellular signaling transduction and interaction, and tissue development. They showed a scheme of the gene to fetus formation in a fascinating way.
León-Campos et al., summarized the current understanding of the role of fundamental principles of cellular differentiation in stem cells facilitated by biomaterial compositions within hydrogel matrices and explored its potential applications in regenerative medicine.
Ture et al., reviewed the promising treatment of sepsis, a life-threatening syndrome through stem cell therapy. It holds the potential to significantly treat infectious diseases and has a positive influence on clinical outcomes.
Undoubtedly, stem cells hold a great promise for regenerative medicine given their ability to proliferate and differentiate into various cell types. Zongjie Wang explained the current practices of assay development to fulfill this demand . Thus the joint venture of biologists, bioengineers, veterinarians, and clinicians can confidently generate quality stem cell products to change the trajectory of tissue degeneration.
We owe our special thanks to all the contributors for their valuable impact in bringing together the eleventh volume of our book. And, we also thank the editorial staff of Bentham Science Publishers, particularly Ms. Asma Ahmed and Mr. Mahmood Alam for their relentless help and support.
List of Contributors
An Introduction to the Use of Embryology in Clinical Practice
Mandana Beigi Boroujeni1,*,Seyyed Amir Yasin Ahmadi2,Ali Fouladi Nashta3,Fataneh Ghafari3Abstract:
Embryology is a part of anatomical sciences investigating formation, differentiation, growth and development of embryos and fetuses. This science is not only limited to the definition above, but it can also be used for human adults involved in perinatology, infertility, congenital defects, cell therapy and personalized medicine. This chapter aims to introduce embryology and its role in the clinical practice of physicians. The linkage of embryology and medicine is an example of the linkage between basic and clinical medical sciences. Entering to this interdisciplinary field opens a novel door for making hypotheses for future studies.
INTRODUCTION
Definitions
Embryology – sometimes called fetology – is a part of anatomical sciences investigating the formation, differentiation, growth, and development of embryos and fetuses. From a wider viewpoint, this science is not limited to embryos, rather it covers perinatal and even postnatal periods. In other words, embryology may be used from conception and continues until the birth of the baby, and also it is indirectly used during lifespan. Indeed, it can help physicians with the embryological basis of diseases. Nowadays, comparative and interdisciplinary approaches are used to find a developmental basis for different diseases in order to discover methods for targeted therapy and precision medicine. Both basic and practical aspects of embryology are used in this regard.
Perinatology – also known as maternal-fetal medicine – is a subspecialty of obstetrics and gynecology associated with maternal and fetal health from conception until a few days after the birth of the baby. However, perinatal care should start before pregnancy. Neonatology is a branch of pediatrics associated with neonatal care and management of neonatal diseases. The neonatal period starts from birth and ends at about one month of age (28 days).
Embryogenesis starts from the fusion of sperms and oocytes. Embryological days, weeks, and months are calculated based on this date. According to this, pregnancy is a 38-week (266-day) process in which the first 8 weeks’ period is called embryogenesis, the first two weeks’ period is called the germinal stage, a period of weeks 3-8 is named the embryonic stage, and the next 30-week period is called the fetal period. In contrast to embryology, in midwifery, obstetrics and gynecology pregnancy is a 40-week (280-day) process in which the first day of pregnancy is the first day of the last menstruation period (LMP). In this system, days, weeks, months and trimesters are usually called “gestational” instead of “embryonic”, although these terms may be used interchangeably. The rationale behind this system is that the exact day of fertilization cannot be determined based on medical history. Therefore, the first day of LMP is a day that can be remembered (Fig. 1). The due date or estimated date of confinement (EDC) is calculated by adding 9 months and 7 days (about 280 days) to the first day of LMP according to Naegele's rule [1]. Since the luteal phase is usually consistent, in patients with a menstruation cycle of more than 28 days, EDC is underestimated (earlier than the real), and in patients with a menstruation cycle of less than 28 days, EDC is overestimated (later than the real); therefore, this formula should be modified patient by patient. Of course, EDC (with or without modification) is merely an estimation for normal pregnancies. In pregnancy complications such as preeclampsia, indications of pregnancy termination as well as being ready for preterm labor should be regarded to reduce fetal death and adverse pregnancy outcomes [2].
Fig. (1)) Pregnancy period based on both embryology and obstetrics. If the fertilization day be 14, the exact difference between these 2 systems will be 2 weeks.Other than natural pregnancies, some patients need assisted reproduction by assisted reproduction technics (ART). In pregnancies assisted with fertility drugs or intrauterine sperm injection (IUI), calculation of EDC is still based on the first day of LMP. In cases of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), EDC is calculated based on retrieval date via adding 266 days (equivalent to an embryological approach to the pregnancy period). If ART is frozen embryo transfer (e.g. 3-day or 5-day embryo), post-fertilization days should be regarded. Estimation of gestational age for planning perinatal cares is via adding 14 days to the retrieval date. In addition, ultrasonographic study may help in the estimation of the gestational age [3].
In the present chapter, when we mention basic embryology we mean embryonic/fetal age, and when we discuss clinical and practical points we usually mean gestational age.
CHAPTER OBJECTIVES
This chapter is aimed to briefly introduce embryology and its role in clinical practice of physicians (including general physicians and medical specialties), briefly. It is expected that after reading this chapter, a physician will be known how to link what has been previously learned about basic embryology with his/her clinical practice including diagnosis and management of congenital defects and management of other diseases with the help of developmental approach. Clinical applications and research horizons are discussed.
CLINICAL APPLICATIONS FOR PHYSICIANS
In general, embryology may be used to investigate how to develop an embryo, knowing chromosomal and gross anatomical abnormalities as well as knowing congenital defects and related pharmacology. Medical embryology is widely used to detect abnormalities before birth and explores the different ways and stages that such abnormalities occur. Here, we also discuss, how embryology can be applied for precision (personalized) medicine by physicians.
Infertility
Infertility is a failure to get pregnant after one year or more of regular unprotected sexual intercourses. Treatment of infertility needs a multidisciplinary approach. A complete history taking helps physicians to differentiate the causes. Infertility may have male or female and sometimes both male and female cause. While most causes of infertility are related to physiology, embryology and anatomy (biological causes), sometimes psychological or psychiatric issue contribute to couples not getting pregnant the natural way.
Biological causes of infertility includes spermatogenesis problems, oogenesis problems, fertilization problems, implantation problems, placentation problems and problems related to durability of pregnancy. Pregnancy loss before gestational week 20 is called spontaneous abortion (miscarriage) and after gestational week 20 is called stillbirth or intrauterine fetal death (IUFD). Other than molecular causes, gross anatomical problems can be the cause as well. For example, uterine defects and malformations include the unicornuate uterus, bicornuate uterus, septate uterus, arcuate uterus and didelphys uterus. Such anomalies are related to the abnormal development of Müllerian ducts.
Perinatal Care
In the word of World Health Organization (WHO), perinatal period starts from gestational week 22 and takes up to day 7 after birth. However, perinatal care starts from conception or even before pregnancy. Perinatal care consists of genetic screening, taking medication history even for over the counter (OTC) drugs, taking history and management of habituations including substance and alcohol use, domestic abuse and violence counseling, management of behavioral health issues including depression, taking history of environmental and occupational exposures, obstetric history including family planning and pregnancy spaces, general physical examinations including cervix and breasts, nutritional assessment and education, vaccinations and screening for infectious diseases, screening for gestational diseases like gestational diabetes mellitus (GDM), checking blood pressure and maternal weight gain at every perinatal visit, ultrasonography routine schedule, biophysical study of fetus (biophysical profile [BPP]), invasive tests including chorionic villus sampling (CVS) and amniocentesis if there is indication, and so forth [4].
Most of the above roles are related to embryology. For example, in nutritional assessment, deficiency of folic acid (vitamin B9) is associated with neural tube defects, or calcium and vitamin D deficiency may cause immunological problems in placenta and therefore, increased risk of preeclampsia (a new unset gestational hypertension after gestational week 20 along with proteinuria or symptoms of organ failure). Genetic disorders and chromosomal abnormalities are studied in embryology. In addition, ultrasonography routine schedule and BPP are based on fetal development in embryology.
Drug history is very important because of fetal consequences. Categories of safety are from A to X levels: A) safe in the first trimester based on human studies, B) safe based on animal studies, C) animal studies have shown adverse effects, however, it may be used in humans according to some potential benefits, D) human studies have shown adverse effects, however, it may be used according to some potential benefits, and X) evidence of fetal abnormalities and should not be used. For example, thalidomide is a group X drug resulting in Amelia (which means lack of limb) and Phocomelia (malformation of arms and legs due to lack of long bone formation).
Abnormalities and Congenital Defects
Teratology is the study of congenital abnormalities. Teratogens are drugs and substances or any other metabolic and infectious agents resulting in teratogenesis (the process of forming congenital defects or malformation). Congenital abnormalities have a wide-spectrum prognosis. Some abnormalities are contrary to survival (after birth or within first five year of life), some abnormalities are chronic with morbidities in life like limb abnormalities, and some others like many cases of congenital heart disease that are usually asymptomatic, however, should be managed.
Antenatal care and antenatal diagnosis methods help physicians to diagnose anomalies during pregnancy. The mission of this chapter is not only the propagation of early detection (for legal pregnancy termination) but also the propagation of medical and surgical managements of such defects to decrease morbidities and increase the quality of life.
Developmental Approach and Cell Therapy
Every human is originated from one zygote. This zygote creates totipotent stem cells, the cells that have potency of self-renewal. In this process, a stem cell is divided into two symmetric stem cells like the mother stem cell without any differentiation. Totipotency means the ability to produce all differentiated cells of an organism. Then morula – the 16 cell stage of an embryo at day 3 after fertilization – is created which has totipotent stem cells. After conversion of morula to blastocysts, the inner mass cells of blastocysts are called pluripotent stem cells. A pluripotent stem cell can be differentiated to any of the three germ layers including endoderm, mesoderm and ectoderm. These layers are created after the formation of blastocyst –more than 128-cell stage of an embryo at day five after fertilization – and each germ layer can create its related tissues and organs. At this time, the stem cells are called multipotent. After birth, the survivors of stem cells are multipotent stem cells and the next levels (i.e. oligopotent and unipotent stem cells), excluding primordial germ cells.
Cell therapy is an application of either stem or differentiated cells for the treatment of diseases. An example of using differentiated cells is the chimeric antigen receptor (CAR) T cell for immunotherapy. CAR T cells are modified T
cells that expressed engineered T cell receptors providing them with the ability to target specific antigens commonly expressed specifically by cancerous cells.
Another part of cell therapy is using stem cells. These stem cells are usually obtained from adult sources and are multipotent. These multipotent stem cells usually have mesodermal sources (such as hematopoietic stem cells), while endodermal and ectodermal stem cells are less available. Mesenchymal stromal cells (MSC) are commonly part of connective tissues such as cartilage, bone and skin, and originate from mesoderm.
There are two approaches to stem cell therapy; using to fill and replace tissue via replication and differentiation of the very injected stem cells, and using their indirect effects such as using their protective paracrine signaling of stem cells[5, 6] as well as using mitochondrial transfer of MSCs (called mitochondrial donation) [6]. For example, MSCs are used in diabetes type 1 and neurodegenerative disorders; but pancreas and nerve system have endodermal and ectodermal basis, respectively. Therefore, the efficacy of MSC therapy in such patients may not be direct treatment.
Another way to repair tissues – both mesodermal-based tissues and even tissues which have a basis other than mesoderm – is the induction of pluripotency in MSCs or even somatic cells. These modified MSCs are called induced pluripotent stem cells (IPSC). IPSC induction can be in vivo (which has safety concerns) or in vitro (with the concern of differentiation efficiency/contamination with other cells than the intended differentiation of target cell). Then, trans-differentiation is used to regenerate endodermal- and ectodermal-based tissues using some specific growth factors. However, safety of these methods is under investigation [7]. A scheme of approach to cell therapy based on current knowledge is shown (Fig. 2).
Molecular Approach and Personalized Medicine
The basis of tissue development and differentiation can be molecular including turning off and turning on of different genes as well as the expression of surface markers. Cluster differentiation (CD) markers are one of the functional markers that help us differentiate between cellular clusters. CD markers can be targeted by monoclonal antibodies and CAR T cells as targeted therapy. Knowing developmental basis of diseases such as cancers can help physicians to find a suitable targeted therapy.
Fig. (2)) Approach to cell therapy. Direct tissue repair means via replication and differentiation of stem cells. Indirect tissue repair means via unknown mechanisms like mitochondrial transfer. MSC: mesenchymal stem cell; IPSC: induced pluripotent stem cell.This molecular approach opens a novel door for personalized medicine. This approach is not restricted to cancer therapy but can be used for common diseases like hypertension. For instance, CD143 – also known as angiotensin converting enzyme (ACE) – is a marker of vascular differentiation. An increase in ACE activity is associated with higher blood pressures. Therefore, captopril – as an ACE inhibitor – is used as an antihypertensive drug. Since ACE is a vital developmental marker, captopril and other ACE inhibitors are forbidden in pregnancy (group X).
Each CD marker is expressed from its gene. These genes may have single nucleotide polymorphisms (SNPs). Genetic association studies have shown different susceptibilities to different diseases for different genotypes of different genes. Cohort studies and quasi-experimental studies (sometimes called non-randomized clinical trials) as well as some randomized controlled trials (RCT) have shown different responses to different drugs for different genotypes of specific genes. Meanwhile, the science of pharmacogenomics was created. However, its research methodology is controversial [8]. The terms pharmacogenomics (or pharmacogenetics) and personalized medicine are usually used interchangeably, although they are different.
Pharmacogenomics and personalized medicine are based on the molecular development of humans. Some genes expressing the functional molecules of development may experience changes during pregnancy. For example, copy number variations (CNV) can be mentioned. However, CNVs are rarely de novo. Changes in CNVs happen primarily during the very early stages of pregnancy, likely the pre-implantation stage [9]. The individual differences based on molecular development are also studied with some other interdisciplinary approaches such as immunogenetics, molecular epidemiology and molecular anthropology [10].
