Unhealthy Stem Cells: When Health Conditions Upset Stem Cell Properties

Abstract

The stem cell field has grown very rapidly during the last decade, offering the promise of innovative therapies to treat disease. Different stem cell populations have been isolated from various human adult tissues, mainly from bone marrow and adipose tissue, but many other body tissues harbor a stem cell population. Adult tissue stem cells are invariably found in discrete microenvironments termed niches, where they play key roles in tissue homeostasis by enabling lifelong optimization of organ form and function. Some diseases are known to strike at the stem cell population, through alterations in their specific microenvironments, making them non-viable. Furthermore, it has been shown that a transformed stem cell population could prompt the development of certain cancers. This review focuses on the potential negative aspects of a range of diseases on the activity of stem cells and how their potential use in cell therapies may be affected.

Cellular regenerative therapy for acquired noncongenital musculoskeletal disorders

“…Stem cells derived from patients with underlying pathologies such as chronic inflammatory (rheumatoid arthritis), degenerative (ageing, osteoporosis), metabolic (obesity, diabetes) and genetic (osteogenesis imperfecta, muscular dystrophy) disorders, are not as effective in promoting healing as those from healthy individuals. [2,8,14,15] This outcome is due, in part, to numerous pathological alterations in the niche microenvironment that may desensitise endogenous stem cells and alter their characteristics to such an extent that they cease to be regenerative agents. [2,15] For example, in a trial of autologous MSC therapy for osteonecrosis, 81% of patients displayed improvements in symptoms, whereas those without improvements had generally entered the trial at a more advanced stage of their disease, including a more severely hypoxic environment.…”

“…[2,8,14,15] This outcome is due, in part, to numerous pathological alterations in the niche microenvironment that may desensitise endogenous stem cells and alter their characteristics to such an extent that they cease to be regenerative agents. [2,15] For example, in a trial of autologous MSC therapy for osteonecrosis, 81% of patients displayed improvements in symptoms, whereas those without improvements had generally entered the trial at a more advanced stage of their disease, including a more severely hypoxic environment. [16] Despite the initial expansion of MSCs in an optimal ex vivo environment with adequate oxygen supply, hips with stage III or IV disease, with poor in vivo oxygen supply to the affected area, progressed.…”

“…Therefore, systemic as well as local conditions may affect the efficacy of stem cell therapy, as stem cells may exhibit functional changes including impaired growth, differentiation and migratory capacity. [2,15,17] A recent review of the literature, on the negative aspects of a range of diseases, indicates that stem cell dysfunction can occur as a result of genomic instability, telomere attrition, senescence, mitochondrial dysfunction, epigenetic changes or loss of proteostasis. [2] There is, furthermore, mounting evidence that the altered microenvironment, established as a result of the transition from health to chronic injury or disease, not only transforms intracellular characteristics, but also adversely affects cellular communication.…”

“…[2,15,17] A recent review of the literature, on the negative aspects of a range of diseases, indicates that stem cell dysfunction can occur as a result of genomic instability, telomere attrition, senescence, mitochondrial dysfunction, epigenetic changes or loss of proteostasis. [2] There is, furthermore, mounting evidence that the altered microenvironment, established as a result of the transition from health to chronic injury or disease, not only transforms intracellular characteristics, but also adversely affects cellular communication. [2,18] It has now become accepted that the regenerative potential of stem cells is mediated largely through their release of biologically active molecules, and the subsequent effect of these on target cells.…”

“…This may be attributed to a number of aspects including poor engraftment and survival, inability of cells to differentiate into the target tissue, and the emerging understanding that, in many cases, an inflammatory or fibrotic host environment with underlying pathology deters the regenerative capacity of applied cells. [1,2] A further complication that hampers progress is that most clinical trials testing cellular regenerative therapies are undertaken in small cohorts and there is variability with regard to the type of stem cell population used, their method of delivery, formulation (combination of cellular and drug therapy), the level of control or randomisation, and even the outcome measures assessed. [1] To aggravate these issues, recent retractions by leading journals of previously lauded stem cell science and its clinical application, [3,4] as well as the proliferation of corrupt clinics exploiting the unrealistic hope of individuals seeking therapies for currently non-treatable diseases, threaten to sabotage this emerging area of regenerative medicine.…”