Stem cells and gene therapy to treat osteogenesis imperfecta: hype or hope
A genetic syndrome that affects the bones
Osteogenesis imperfecta (OI) is an inherited disease occurring in 1 / 10,000 births and characterized by osteopenia (bone loss) and skeletal fragility (fractures). Secondary features include short stature, skeletal deformities, blue sclera, and dentinogenesis imperfecta. (1) There is great clinical variability in OI, and the severity ranges from mild to fatal, depending on the radiological features. Genetically, OI is a collagen syndrome. Type I collagen is a heterotrimeric helical structure synthesized by bone-forming cells (osteoblasts), and it is the most abundant protein in the organic skeletal matrix. (2) The synthesis of type I collagen is a complex process. (3) Collagen molecules are crosslinked into fibrils (which provide tensile strength to bones). These are then mineralized by hydroxyapatites (which provide compressive strength) and assembled into fibers.
Dominant mutations in the COL1A1 or COLA1A2 genes are responsible for up to 90% of all cases of OI. These mutations (over 1000 of which have been identified) lead to an alteration in the structure and production of collagen, resulting in quantitative or qualitative defects in the extracellular bone matrix (ECM). Mutations in the structure of ECM have serious health consequences because the skeleton protects visceral organs and the central nervous system and provides structural support. Bones also store fat in the yellow bone marrow located in the medullary cavity, while the red marrow located at the end of long bones is the site of hematopoiesis. In addition, ECM constitutes a reservoir of phosphate, calcium and growth factors, and participates in the trapping of dangerous molecules.
The rationale for cell therapy
Stem cell therapy for OI aims to improve bone quality by harnessing the ability of mesenchymal stem cells (MSCs) to differentiate into osteoblasts, with the rationale that donor cells would graft into bone, produce collagen normal and would work as a cell replacement. Stem cells have therefore been proposed for the treatment of OI (4) and, in particular, therapy with prenatal fetal stem cells (fetal stem cells injected into a fetus, i.e. fetal to fetal), which offers a promising avenue for effective treatment. (5) Human fetal stem cells are more primitive than stem cells isolated from adult tissues and exhibit advantageous characteristics over their adult counterparts, i.e., they possess a higher level of plasticity, se more readily differentiate into specific lineages, grow faster, senescent later, express higher levels of adhesion molecules, and are smaller in size. (6,7) Prenatal cell therapy takes advantage of the small size of the fetus and its immunological naivety. In addition, stem cells delivered in utero benefit from the expansion of endogenous stem cells and can prevent organ damage before irreversible damage. (8)
However, the human fetal stem cells used are isolated either from fetal blood collected by cardiac puncture, during the termination of pregnancy, or during the current pregnancy, although using an invasive procedure associated with a high risk of cancer. morbidity and mortality for the fetus and mother (9). Fetal cells can also be isolated from the liver in the first trimester (after termination of pregnancy) and these cells are currently being used in the Boost Brittle Bones Before Birth (BOOSTB4) clinical trial, which aims to study safety and efficacy. of fetal mesenchymal stem cell transplantation. prenatal and / or early postnatal life to treat severe osteogenesis imperfecta (OI) (10). Alternatively, fetal stem cells can be isolated during the current pregnancy from amniotic fluid, either during amniocentesis in mid-trimester or at birth (11,12) or from the chorionic villi of the placenta during pregnancy. first trimester chorionic villus sampling (13).
We have demonstrated that human fetal stem cells isolated from first trimester blood have greater osteogenic differentiation potential compared to adult stem cells isolated from bone marrow and first trimester fetal stem cells isolated from liver. We have shown that in utero transplantation of these cells in an experimental model of severe OI resulted in a drastic 75% decrease in the incidence of fracture rate and skeletal fragility, as well as an improvement in resistance. and the quality of the bones. (14) A similar result was obtained using the placenta. Fetal-derived stem cells (15) and amniotic fluid stem cells after perinatal transplantation in experimental models. (16.17)
The future of IO
Understanding the mechanisms of action of donor cells will allow donor cells to be designed with greater efficiency in stimulating bone formation and strengthening the skeleton. Despite their potential to differentiate down the osteogenic lineage, there is little evidence that donor cells contribute to bone regeneration through direct differentiation, due to the very low level of donor cell transplantation reported in all of our studies. When placed in an osteogenic microenvironment in vitro, fetal stem cells readily differentiate into osteoblasts and produce wild-type collagen molecules. However, there is not enough evidence that the collagen molecules of donor cell origin contribute to the formation of host bone ECM to confer superior fracture resistance.
It is now well accepted that stem cells can influence the behavior of target cells through the release of paracrine factors and, therefore, indirectly contribute to tissue regeneration. We have recently shown that donor stem cells stimulate the differentiation of resident osteoblasts, which could not reach complete maturity in the absence of stem cell treatment. (16,17) We are now focusing our efforts on understanding the precise molecular mechanisms by which donor cells improve skeletal health to counteract bone fragility caused by various mutations responsible for OI.
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