Very useful article summarizing challenges of regeneration in a historical context

waynakyo

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http://onlinelibrary.wiley.com/doi/10.1111/exd.12334/full

brings perspective and some hope...

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]You have free access to this content[/FONT][h=1][FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]At the dawn of hair research – testing the limits of hair follicle regeneration[/FONT][/h]


[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]The hair follicle has emerged as one of the leading experimental models for studying mechanisms of tissue regeneration in adult mammals. The hair growth cycle is a prominent physiological regenerative process, wherein each hair follicle cyclically transitions through complex phases of remodelling, each time producing a new hair shaft. In addition to physiological regeneration, hair follicles are able to regenerate after injury, such as following transection and even when dissociated into a single cell suspension. Indeed, dissociated epithelial and mesenchymal cells can effectively reassemble into new, fully functional hair follicles when recombined in vivo [1].[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]The latter cell-based reconstitution experiments generated considerable excitement that hair follicles can be multiplied from limited donor material by expanding epithelial and mesenchymal cells in vitro and then implanting them into the donor site, such as into scars or scalp skin of patients with androgenetic alopecia. Follow-up studies using human instead of mouse cells painted a more complex picture, wherein this high hair-inducing ability displayed by mouse dermal papilla cells is not readily replicated by human cells under similar experimental settings[2, 3].[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]There is an ongoing effort to try to overcome the low inductive potential of human dermal papilla cells and adapt cell-based hair reconstitution techniques into clinical settings. Only recently, conclusive evidence for the ability of human cells to reassemble into new functional hair follicles was provided [4-7]. To achieve human hair reconstitution, Thangapazham et al. [5] and Higgins et al. [8] improved hair-inducing properties of adult dermal papilla cells in vitro by placing them into dermal–epidermal composites or growing them in three-dimensional spheroid cultures, respectively.[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]As the field continues to edge closer towards developing clinically successful strategies for cell-based hair restoration, there is a growing need to better understand the signalling basis behind the inductive properties of hair follicle mesenchyme. However, it is only within the last couple of years that genetic tools have been made available to hair researchers to study the mesenchymal aspect of complex signalling interactions underlying hair follicle development and regeneration [9-11].[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]As we anticipate our knowledge of hair follicle mesenchyme to increase exponentially, it is helpful and educational to reflect on the fact that a lot of what we currently know came from the pioneering studies by Roy Oliver dating back to 1966–67 [12, 13]. In a series of ingenious experiments performed on the model of rat vibrissa, Oliver showed that the hair follicle's dermal papilla, the key regulatory centre of hair follicle growth, can fully regenerate following its amputation. This provided the first evidence in support of the dermal sheath, the dermal layer enveloping the hair follicle, being the reservoir of progenitor cells able to readily differentiate towards dermal papilla cell type [12]. Close functional similarities between dermal papilla and dermal sheath were later confirmed by others [14-17], and the ability of dermal sheath to substitute for dermal papilla for the purposes of hair follicle induction was demonstrated in a proof-of-principle human study [18].[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]Importantly, the original studies by Oliver showed that the ‘morphogenetic information’ about hair follicle size and timing of the hair growth cycle is not restricted to the dermal papilla, but also resides within the adjacent dermal sheath. Indeed, vibrissae follicles that regenerated after dermal papilla amputation produced new hair shafts of nearly normal length, indicating an intact hair cycle clock [12]. Furthermore, by amputating vibrissae at different levels and studying their subsequent regeneration, Oliver mapped out the functional properties of the dermal sheath along the long axis of the hair follicle, wherein the lower one-third can induce follicle regeneration, while the upper two-thirds are generally non-inductive [12]. The full text is available via http://dev.biologists.org/content/15/3/331.long.[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]Today, nearly 50 years since these original experiments had been published, surprisingly little new insight has been gained into the biology of dermal sheath cells, largely held back by the scarcity of dermal sheath-specific genetic tools [19]. In the future, it will be particularly interesting to establish whether the dermal sheath primarily acts as the niche for mesenchymal stem cells of the dermal papilla. In addition, the dermal sheath exerts important other functions, such as regulating the behaviour of epithelial cells in the outer root sheath, including the downward bound migration of epithelial stem cell progeny during anagen, the active hair growth phase [20]. Also, comparative gene expression profiling between hair-inducing lower and non-inducing upper dermal sheath cells should yield novel mesenchymal determinants of inductivity with practical application for boosting efficacy of human hair reconstitution assays.[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]In his follow-up 1967 study, Oliver showed that dermal papillae can rescue the regenerative potential of amputated vibrissae follicles, which otherwise fail to regenerate on their own [13]. For the first time and perhaps without fully realizing these implications, this landmark study positioned epithelial progenitor cells into the upper segment of the hair follicle, away from the hair matrix. Only decades later was it conclusively shown that the upper segment of the follicle, known as the bulge, contains bona fide hair follicle stem cells [21], and when purified and mixed with the inductive mesenchyme, these cells are able to efficiently reconstitute new hairs [22].[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]Thus, Oliver's original study established the basic requirements for successful hair regeneration – interposition of inductive mesenchyme with competent, hair-fated epithelium. Indeed, while under some experimental settings the dermal papilla can induce lineage conversion of non-hair-fated epithelia, such as in footpad skin, into a hair follicle-type differentiation pathway [15, 23], it is recognized that clinically successful cell-based hair follicle neogenesis protocols call for hair-fated epithelial progenitors, such as bulge stem cells [22].[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]Lastly, by providing a detailed positional map of vibrissae follicles and characterizing the growth rate and whisker length values at all major whisker positions, Oliver's work characterized and established vibrissa follicles as preferred highly instructive experimental model in hair research [12] (Fig. 1a,b). Even now, in the age of modern day genetics and cell biology, the vibrissa follicle remains one of the experimental models of choice in skin and hair biology (reviewed in details in Ohyama et al. [24], recognized for its intricate microanatomy and prominent stem cell compartment [25, 26].[/FONT]

[FONT=Verdana, Arial, Tahoma, Calibri, Geneva, sans-serif]Figure 1. The model of vibrissae hair follicle regeneration. (a) Positional map of vibrissae follicles detailed by Oliver [11]. (b) Schematic drawing of whisker hair follicle with major anatomical structures. (c) Schematic drawing of vibrissa hair follicle amputation experiments developed by Oliver: amputation of dermal papilla or lower one-third of the follicle length results in regeneration, while regeneration fails of more than one-third of the follicle is removed. In the latter scenario, regeneration can be rescued by transplanting dermal papilla.[/FONT]
 

IDW2BB

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More from the mouse that may help our cause one day. Couple years old but interesting as he'll.


http://www.ncbi.nlm.nih.gov/pubmed/?term=Pref-1+hair


Extracellular matrix-derived products modulate endothelial and progenitor cell migration and proliferation in vitro and stimulate regenerative healing in vivo.
Vorotnikova E1, McIntosh D, Dewilde A, Zhang J, Reing JE, Zhang L, Cordero K, Bedelbaeva K, Gourevitch D, Heber-Katz E, Badylak SF, Braunhut SJ.
Author information

Abstract
Most adult mammals heal without restorative replacement of lost tissue and instead form scar tissue at an injury site. One exception is the adult MRL/MpJ mouse that can regenerate ear and cardiac tissue after wounding with little evidence of scar tissue formation. Following production of a MRL mouse ear hole, 2mm in diameter, a structure rapidly forms at the injury site that resembles the amphibian blastema at a limb amputation site during limb regeneration. We have isolated MRL blastemal cells (MRL-B) from this structure and adapted them to culture. We demonstrate by RT-PCR that even after continuous culturing of these cells they maintain expression of several progenitor cell markers, including DLK (Pref-1), and Msx-1. We have isolated the underlying extracellular matrix (ECM) produced by these MRL-B cells using a new non-proteolytic method and studied the biological activities of this cell-free ECM. Multiplex microELISA analysis of MRL-B cell-free ECM vs. cells revealed selective enrichment of growth factors such as bFGF, HGF and KGF in the matrix compartment. The cell-free ECM, degraded by mild enzyme treatment, was active in promoting migration and proliferation of progenitor cells in vitro and accelerating wound closure in a mouse full thickness cutaneous wound assay in vivo. In vivo, a single application of MRL-B cell matrix-derived products to full thickness cutaneous wounds in non-regenerative mice, B6, induced re-growth of pigmented hair, dermis and epidermis at the wound site whereas scar tissue replaced these tissues at wound sites in mice treated with vehicle alone. These studies suggest that matrix-derived products can stimulate regenerative healing and avert scar tissue formation in adult mammals.
Copyright © 2010 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
 
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