Hox-Positive Adult Mesenchymal Stromal Cells: Beyond Positional Identity

Abstract

Homeotic genes (Hox) are universal regulators of the body patterning process in embryogenesis of metazoans. The Hox gene expression pattern (Hox code) retains in adult tissues and serves as a cellular positional identity marker. Despite previously existing notions that the Hox code is inherent in all stroma mesenchymal cells as a whole, recent studies have shown that the Hox code may be an attribute of a distinct subpopulation of adult resident mesenchymal stromal cells (MSC). Recent evidence allows suggesting a "non-canonical" role for Hox gene expression which is associated with renewal and regeneration in postnatal organs after damage. In tissues with high regenerative capacity, it has been shown that a special cell population is critical for these processes, a distinctive feature of which is the persistent expression of tissuespecific Hox genes. We believe that in the postnatal period Hox-positive subpopulation of resident MSC may serve as a unique regenerative reserve. These cells coordinate creation and maintenance of the correct structure of the stroma through a tissue-specific combination of mechanisms. In this article, we summarize data on the role of resident MSC with a tissue-specific pattern of Hox gene expression as regulators of correct tissue reconstruction after injury.

HOX genes in stem cells: Maintaining cellular identity and regulation of differentiation

“…However, rather than accounting for stem cell type-specific functions, HOX genes specify various regional properties of a tissue along the rostral-caudal axis by regulating a wide range of cellular activities such as proliferation and differentiation, cellular adhesion, migration and invasion, as well as cell death ( Parrish et al, 2009 ). The persisting HOX expression profiles of the different tissue-specific MSCs strongly suggest that those specific HOX profiles are of particular importance for the functioning of tissues throughout adult life with resident HOX-expressing MSCs as leading regulators of embedding stroma renewal and regeneration ( Kulebyakina and Makarevich, 2020 ). Following a rough classification along the cranial-caudal direction, HOX1-4 paralogues were shown to act predominately in cranial tissues, followed by HOX5-6 in subsequent upper sternal tissues, and HOX7-8 in lower sternal and abdominal tissues, whereas the paralogues HOX9-13 represent HOX genes building up HOX codes in caudal body parts and extremities ( Kulebyakina and Makarevich, 2020 ).…”

“…The persisting HOX expression profiles of the different tissue-specific MSCs strongly suggest that those specific HOX profiles are of particular importance for the functioning of tissues throughout adult life with resident HOX-expressing MSCs as leading regulators of embedding stroma renewal and regeneration ( Kulebyakina and Makarevich, 2020 ). Following a rough classification along the cranial-caudal direction, HOX1-4 paralogues were shown to act predominately in cranial tissues, followed by HOX5-6 in subsequent upper sternal tissues, and HOX7-8 in lower sternal and abdominal tissues, whereas the paralogues HOX9-13 represent HOX genes building up HOX codes in caudal body parts and extremities ( Kulebyakina and Makarevich, 2020 ). An example for the association of HOX gene expression within the organization of tissue-specific structures and features comes from VW-MSCs ( Klein et al, 2013 ).…”

Comparative analysis of mesenchymal stem/stromal cells derived from human induced pluripotent stem cells and the cognate umbilical cord mesenchymal stem/stromal cells

“…Previous study has showed that homeobox (Hox) genes were key regulators of the multiorgan development in embryogenesis and has a crucial role in nervous system development and function [ 33 ]. Recent studies have shown that the Hox code might be an attribute of a distinct subpopulation of tissues resident mesenchymal stromal cells (MSC), which played a crucial role in stroma renewal and tissue regeneration [ 34 , 35 ]. In our study, the Hox gene family members, including HOXD3 , HOXD4 , HOXD9 , HOXD10 , HOXD11 , HOXD12 also HOXA3 , HOXA5 , HOXA6 , as well as HOXB8 , HOXB9 and HOXC12 were highly expressed in iMSCs compared to UMSCs ( Fig.…”

“…Recent studies have indicated HOX-positive cells may represent a distinct subpopulation of adult resident mesenchymal stromal cells (MSCs) in vivo , which is crucial for reconstructing stroma and tissue regeneration [ 34 , 35 ]. Moreover, large studies had indicated that the large family of Hox gene has a key role in nervous system development and function [ 33 , 41 ].…”

Resolving Darwin’s Dilemma over Natural Selection, Individual Benefit and Aging-on<em> </em>the Natural Selection of Organismal Aging

“…These cells coordinate creation and maintenance of the correct structure of the stroma through a tissue-specific combination of mechanisms. Thus, homeotic gene expression in adult stromal cells is not limited to storing positional information as during development, but also functions as master regulators of many processes affecting cell phenotype and, thus functional characteristics [52].…”