Sex Determination in Homo sapiens as a Multi-Step Process: Potential for Development of Variants and Sex Differences in Disease Risk

Reproduction via cis-binary mechanisms appears to have evolved fairly early in the evolution of complex organisms, and a system committed to prior to evolution of humans. While the evolution of a chromosomal-specific approach has been a successful strategy for survival of a large variety of species including humans, the fidelity of sex determination leading to 100% cis-binary outcomes is not achieved in many species, with evidence for homosexual or bisexual behaviour evident in more than 1500 species. Thus, such outcomes indicates that sex determination is a multi-step process and not a single event, and as such, could lead to the appearance of variants during the process which developed much earlier than humans. Variants could arise either due to intrinsic variation in the steps of determination, or also be influenced by environmental factors of a biological or psychological nature. In contrast to homosexual variants which do not require interventions such as hormone therapy or surgery, expression of gender dysphoria, is more based in psychology, but also has biological underpinnings and can be influenced by such hormonal interventions and surgery. While the numbers of those with gender dysphoria is small (~0.6% - 1.0% of population), the attention given to this issue raises the possibility of biological and psychological environmental factors impacting the emergence of some of those expressing gender dysphoria. Furthermore, transitioning from male-to-female or female-to-male can have consequences regarding disease risks latter in life, including the appearance of autoimmune diseases. This review will attempt to review some of the evidence regarding sex determination, discuss why the system has potentially not been improved upon during evolution, how a potential role for sex chromosome function on neurodevelopment may be central to variation in humans, and how commitment to the current strategy is likely integrated into other sex-related events such as puberty, pregnancy, and menopause to ensure species survival. It will also discuss how variants in sex determination could contribute to sex differences in disease risk and how epigenetic modifications could play a role in such risk. .

Why Mesenchymal Stem/Progenitor Cell Heterogeneity in Specific Environments? <br/>—Implications for Tissue Engineering Applications Following Injury or Degeneration of Connective Tissues

Mesenchymal stem/progenitor cells (MSC/MPC) from a variety of tissue sources (bone marrow, adipose tissue, fat pads, synovial membranes, synovial fluid, skin, muscle and periosteal tissue) have been widely applied for tissue engineering applications to generate replacements for injured or degenerated tissues. Alternatively, they have also been injected as free cells in an attempt to facilitate in vivo repair. Nearly all studies reported have used mixed cell populations of MSC/MPC, usually defined by cell surface phenotypes and/or functional ability to differentiate towards multiple cell lineages. Using more detailed cell surface phenotyping and limiting dilution approaches to isolate individual MSC/MPC clones have indicated that such mixed cell populations are very heterogeneous. In addition subsets of cells from different sources may have epigenetic modifications. While it is clear that MSC/MPC cells exhibit heterogeneity, the question of why this is the case has not been well addressed. This review will address some of these issues, as well as provide some insights into the implications when using such diverse cells for tissue engineering applications.

Evidence for a Potential “Knee-Eye-Brain Axis” Involved in Mobility and Navigation Control: Knee Injury and Obesity May Disrupt Axis Integrity

Humans depend on the coordinated activity of their lower extremities for mobility, an essential feature of Homo sapiens. In addition, they use vision to use this mobility to successfully navigate through their environment. During development, mobility appears to mature first, and then it is coordinated with navigation. Thus, the two, mobility and navigation are likely interdependent in function. Recent studies have indicated that compromising the integrity of the knee, a central element of the lower extremity motion segment, can lead to molecular alterations in both the cornea including the central cornea where light passes, as well as the interior of the eye (the vitreous humor). Not all insults to the knee lead to reproducible alterations in the eye, indicating some specificity in the response. In addition, it was recently reported that alterations to the cells in the vitreous humor occur following dietary induction of obesity in a rat model. As humans with obesity, as well as arthritis of the knee are at risk for ocular involvement and exhibit altered gait characteristics, the clinical and preclinical data raise the possibility of a “knee-eye-brain axis” to control or regulate mobility and navigation. Better delineation of such an axis could have implications for variations in control during maturation, and well as during aging when vision and mobility can be compromised, with increased risk for serious falls and failure to successfully navigate the environment.

Is Adipocyte Differentiation the Default Lineage for Mesenchymal Stem/Progenitor Cells after Loss of Mechanical Loading? A Perspective from Space Flight and Model Systems

Mesenchymal stem/progenitor cells (MSC/MPC) are found in many tissues and fluids including bone marrow, adipose tissues, muscle, synovial membranes, synovial fluid, and blood. Such cells from different sources can proliferate and differentiate into different lineages (e.g. osteogenic, chondrogenic and adipogenic) after suitable stimulation. However, details regarding the regulation of MSC/MPC proliferation and differentiation status are still unclear and it is likely that regulation involves both biological and mechanical influences in the different environments. It has been noted that in humans and preclinical animal models that exposure to microgravity/space flight or prolonged bed rest (a surrogate for microgravity) can lead to infiltration of skeletal muscle and bone marrow with fat. Similarly, in preclinical models treated with multiple intramuscular injections of Botulinum Toxin A to induce muscle weakness and atrophy, there is also an infiltration of the muscle with fat. The origins and basis for these fat deposits are largely unknown, but there is a possibility that the altered mechanical and biological environments lead to dysregulation of MSC/MPC and progression to preferential differentiation towards the adipocyte lineage. Furthermore, loss of MSC regulatory control by either mechanical and/or biological factors may also contribute to their involvement in obesity development and progression. Thus, the utility of using MSC/MPC from some sources for tissue engineering purposes may be compromised and further research regarding optimal loading for tissue engineering purposes is likely warranted.

Treatments for fibrosis development and progression: Lessons learned from preclinical models and potential impact on human conditions such as scleroderma, pulmonary fibrosis, hypertrophic scarring and tendinopathies

Progressive fibrosis of a tissue or organ in response to a damaging insult may result in loss of organ function if the acute response is excessive, or a chronic fibrotic response is initiated due to the persistence of the insult. In the author’s laboratory over the past several years, a number of preclinical models of fibrosis or fibrogenic responses have been characterized for the effectiveness of various treatment approaches to either prevent or impede fibrosis development and progression to identify commonalities and translatable research directions that could provide insights into human diseases. These have mainly included either chemically induced pulmonary fibrosis models or overt physical injury models in rats, pigs and rabbits. Some preliminary studies in human populations have also been undertaken. The interventions evaluated have included fibrinolytic agents and drugs targeting specific cell populations. The results indicate that some approaches lend themselves to modifying fibrotic reactions in some models and not others, while others may have a more generalized impact on fibrogenic responses due to interference with abnormal cell functions in the injury environment.

Are We Learning as Much as Possible from Spaceflight to Better Understand Health and Risks to Health on Earth, as Well as in Space?

The objective of this review is to discuss the changes in human biology and physiology that occur when humans, who evolved on Earth for millions of years, now are subjected to space flight for extended periods of time, and how detailing such changes associated with space flight could help better understand risks for loss of health on Earth. Space programs invest heavily in the selection and training of astronauts. They also are investing in maintaining the health of astronauts, both for extensive stays in low earth orbit on ISS, and in preparation for deep space missions in the future. This effort is critical for the success of such missions as the N is small and the tasks needed to be performed in a hostile environment are complex and demanding. However, space is a unique environment, devoid of many of the “boundary conditions” that shaped human evolution (e.g. 1 g environment, magnetic fields, background radiation, oxygen, water, etc). Therefore, for humans to be successful in space, we need to learn to adapt and minimize the impact of an altered environment on human health. Conversely, we can also learn considerably from this altered environment for life on earth. The question is, are we getting the maximal information from life in space to learn about like on earth? The answer is likely No, and as such, our “Return on Investment” is not as great as it could be. Even though the number of astronauts is not large, what we can learn from them could help shape new questions for research focused on health for those on earth, as well is contribute to “precision health” from the study of astronaut diversity. This latter effort would contribute to both the health of astronauts identifying risks, as well as contribute to health on earth via better understanding of the human genome and epigenome, as well as factors contributing to risk for diseases on earth, particularly as individuals age and regulatory systems become altered. Better use of the International Space Station, and similar platforms in the future, could provide critical insights in aging-associated risks for loss of health on Earth, as well as promote new approaches to using precision medicine to overcome threats to health while in space. To achieve this goal will likely require advanced approaches to collecting such information and use of more systems biology, systems physiology approaches to integrate the information.

Influence of Space Environments in System Physiologic and Molecular Integrity: Redefining the Concept of Human Health beyond the Boundary Conditions of Earth

Space travel since the 1960s has led to a number of physiological alterations to homeostasis in astronauts. Extensive variation in the pattern of responses observed has led a concerted effort to develop countermeasures to overcome such changes and restore homeostasis, and thus “health” is defined as more “Earth-like”. These adaptations to a space environment by a species which evolved and normally exists in the 1 g environment, the geomagnetic field, and background radiation of Earth are viewed as threats to health as defined by the conditions of Earth. Exposure to space can lead to alterations in genomic stability and epigenetic signatures, alterations which could redefine “health” and responses to risks for loss of health for those who will return to Earth. In contrast, in the future individuals born in non-Earth space environments will likely develop an integrated metabolic set point defined by those conditions. They will thus be shaped by both the local environments, and space-associated genomic/epigenomic alterations to their parents. Therefore, such an altered set point for those born and raised in non-Earth space environments will potentially have physiological and molecular consequences which may lead to either new evolutionary adaptation, or to compromise of long term health due to drastically altered set points for integrated physiologic function which is at odds with the evolutionary history of humans. The implications of the two options will be critical for defining “health” in altered environments encountered during space ventures, as well as providing insights into the regulation of human integrity at the physiological level. Therefore, the definition of “health” is dependent on the boundary conditions surrounding development and maturation, and is a dynamic concept.

Perspectives on endogenous and exogenous tissue engineering following injury to tissues of the knee

The knee is a multi-component organ system comprised of several tissues which function coordinately to provide mobility. Injury to any one component compromises the integrity of the system and leads to adaptation of the other components. Over time, such events often lead to dysfunction and degeneration of the knee. Therefore, there has been considerable research emphasis to repair injured components in the knee including cartilage, menisci, and ligaments. Approaches to improving healing and repair/regeneration of knee tissues have included surgery, anti-sense gene therapy, injection of growth factors and inflammatory cytokine antagonists, transplantation of in vitro expanded chondrocytes, enhancement of endogenous cells via microfracture, injection of mesenchymal stem cells, and implantation of in vitro tissue engineered constructs. Some of these approaches have lead to temporary improvement in knee functioning, while others offer the potential to restore function and tissue integrity for longer periods of time. This article will review the status of many of these approaches, and provide a perspective on their limitations and potential to contribute to restoration of knee function across the lifespan.

Obesity, the Obesity Epidemic, and Metabolic Dysfunction: The Conundrum Presented by the Disconnect between Evolution and Modern Societies

Currently, there is an obesity epidemic in the developed world, with both adults and children being affected. The consequences of this epidemic on health and health outcomes have impact at multiple levels, and it is increasing. The basis for this epidemic, which appears to have emerged with significance ~40 - 50 years ago, is unknown but is believed by many to have much of its basis in poor diets and inactivity/sedentary behaviour. Analysis of the human genome has revealed >100 loci which exhibit risk for development of obesity. Why there are so many loci, and how they benefited humans evolutionarily are unknown. In spite of these limitations, there are urgent needs for effective short-term interventions to assist those with obesity, as well as longer-term needs to effectively prevent development of obesity. For the former, personalized exercise programs, use of prebiotics, optimal nutrition and surgical interventions can be effective for some individuals but more interventions that address cause are also needed. For longer term solutions more detailed genetic and epigenetic understanding of risk will be required. An attractive speculation is that the genomic risk factors for obesity (>100 identified) have been retained evolutionarily to address acute metabolic needs and current conditions have converted such risks to a chronic state, making reversal more difficult and with more consequences, including possible epigenetic modifications of risk genes. Other contributing factors to chronic obesity could also relate to chemical disruptors in the environment over the past 50+ years which may impact metabolic regulation via the established risk genomic risk factors or new variants. Therefore, to effectively control this high impact epidemic of obesity likely requires a more detailed genetic and epigenetic analysis of families with obesity and analysis of isolated populations, as well as a more thorough investigation of chemicals capable of being metabolic disruptors in this regard. Thus, the long-term solution(s) to the obesity epidemic will require a concerted multidisciplinary approach that may be more complex than just becoming more active and avoiding sedentary behavior.

Human Heterogeneity and Survival of the Species: How Did It Arise and Being Sustained?—The Conundrum Facing Researchers

Current humans, Homo sapiens, are genetically and epigenetically very heterogeneous, and subsequently also biologically and physiologically heterogeneous. Much of this heterogeneity likely arose during evolutionary processes, via various iterations of humanoid lineages, and interbreeding. While advantageous from a species perspective, the heterogeneity of humans poses serious challenges to researchers attempting to understand complex disease processes. While the use of inbred preclinical models makes the research effort more effective at some levels, the findings are often not translatable to the more heterogeneous human populations. This conundrum leads to considerable research activity with inbred preclinical models, but modest progress in understanding many complex human conditions and diseases. This article discusses several of the issues around human heterogeneity and the need to change some directions in preclinical model research. Using newer Artificial Intelligence and Machine Learning approaches can begin to deduce important elements from the complexity of human heterogeneity.

Perspective: Is It Time to Rename MSC (Mesenchymal Stem Cells/Medicinal Signaling Cells) with a Name that Reflects Their Combined <i>In Vivo </i>Functions and Their <i>In Vitro </i>Abilities?—Possibly “Pluripotent Mesenchymal Regulatory Cells (PMRC)”

Over 30 years ago, it was reported by Caplan that cells could be found in various adult tissues and fluids of a variety of species that could be induced in vitro to progress towards lineages such as chondrogenesis, osteogenesis and adipogenesis with different “cocktails” of reagents. These cells were called Mesenchymal Stem Cells (MSC) to reflect this pluripotency. After 30 years of intense research effort to directly use such cells for the repair or regeneration of damaged or injured tissues, the effort has met with limited in vivo success, but their use for in vitro tissue engineering has met with some success. This failure to live up to expectations for in vivo differentiation success has led Caplan to recently rename these cells Medicinal Signaling Cells (MSC) to reflect other abilities of these cells to secrete mediators and release exosomes containing biologically active molecules that can influence their neighboring cells in a paracrine manner. However, neither of these names completely captures the combined apparent in vivo functioning of MSC and their in vitro abilities to exhibit pluripotent behavior. Thus, it is suggested, based on the attributes of these cells and their tissue and clonal heterogeneity, that an alternative name be applied to these cells and they be described as Pluripotent Mesenchymal Regulatory Cells (PMRC). This name reflects their regulatory function as pericytes in tissues, as well as their well-known immunoregulatory activity when injected into the intra-articular space and their influence on activities such as wound healing. It also reflects their ability to differentiate along several different lineages to facilitate tissue engineering approaches for tissue repair.