Retrodifferentiation: From Concept to Bedside Stem Cell Therapy
Pp. 3-35 (33)
DOI:
10.2174/9781681084350117040003
Author(s):
Ilham Saleh Abuljadayel TriStem UK Limited, 571 Finchley Road, Unit 320, London NW3 7BN, England.
Affiliation:
Abstract
Epimorphic regeneration is a process by which damaged tissues or severed
body parts are restored to the original. This type of sophisticated regeneration is
observed in urodeles and fetal mammals. For example, through this process, an
amputated limb of a salamander can be restored, by re-growing an exact replica,
irrespective of its age. During limb epimorphic regeneration: committed mesenchymal
cells at the stump site dedifferentiate, forming a cluster of heterogeneous population of
stem cells, known as the blastema. Upon blastema integration, positioning and
expansion, constituent cells embark on redifferentiation and remorphogenesis to restore
the lost appendage. Similar to epimorphic regeneration is retrodifferentiation in human
leukocytes. In response to ligation of monomorphic regions of MHC class II antigens
with monoclonal antibody CR3/43, human leukocytes retrodifferentiate into a variety
of heterogeneous stem cell types belonging to the mesoderm, ectoderm or endoderm
lineage, depending on culture media and conditions. During this process, leukocytes
lose lineage-associated markers home and undergo homocytic aggregation, upregulate
expression of stem cell antigens, and subsequently redifferentiate to give rise original
tissue or, transdifferentiate into a different tissue altogether. The hematopoietic
retrodifferentiated stem cells have been shown to engraft an animal host in two proofs
of principle clinical studies, demonstrating long-term engraftment and safety in
acquired aplastic anaemia, while transient amelioration of beta thalassemia major was
also observed. Binding of MHC class II antigens on leukocytes with the monoclonal
antibody CR3/43 appears to emulate stress and injury in human tissue in vitro, similar
to limb amputation in salamander. The ease by which various stem cell types can be
generated from human peripheral blood has allowed the design of various kits to
guarantee the specificity, sterility and efficacy of stem cells production for various clinical and research applications. The robustness and efficacy of the
retrodifferentiation process in generating unprecedented quantities of stem cells
belonging to the three germ layers will enable organ and tissue reconstruction ex vivo,
using bio-printing and various scaffold materials. Epimorphic regeneration and
retrodifferentiation both have the capacity to recreate and reconstruct tissue with
precise positional integration of cells in such a way that will enable us to heal without
scars and to understand how to maintain tissue integrity and architecture in the face of a hostile environment.
Keywords:
Axolotl, Bioprinting, Blastema, Bone, Dedifferentiation, Ectoderm
Endoderm, Epimorphic Regeneration, Hematopoietic, Hepatocytes, Histogenesis,
Human leukocytes, Mesenchymal, Morphogenesis, Neurons, Pluripotent,
Positional integration, Regeneration, Retrodifferentiation, Salamander,
Scaffolding, Stem Cells, Tissue Repair, Transdifferentiation.