Could humans ever regenerate limbs?

February 10, 2016

Just lopped off your ring finger slicing carrots (some time in the future)? No problem. Just speed-read this article while you’re waiting for the dronebulance. …

“Epimorphic regeneration” — growing digits, maybe even limbs, with full 3D structure and functionality — may one day be possible. So say scientists at Tulane University, the University of Washington, and the University of Pittsburgh, writing in a review article just published in Tissue Engineering, Part B, Reviews (open access until March 8).

The process of amphibian epimorphic regeneration may offer hints for humans. After amputation, the wound heals to form an epidermal layer, the underlying tissues undergo matrix remodeling, and cells in the region secrete soluble factors. A heterogeneous cell mass, or blastema, forms from the proliferation and migration of cells from the adjacent tissues. The blastema then gives rise to the various new tissues that are spatially patterned to reconstruct the original limb structure. (credit: Lina M. Quijano et al./Tissue Engineering Part B)

Epimorphic generation occurs in certain animals, such as salamanders and frogs, which are able to regenerate limbs, tails, jaws, and even eye lenses; and in deer antlers and mouse ears.

Turns out there are also rare cases of children and young adults who have had tips of digits regenerated. And there are specific “steps of epimorphic regeneration to promote the partial or complete restoration of a biological digit or limb after amputations,” the scientists believe.

Epimorphic regeneration in the murine (type of mouse) digit is level-specific and provides an opportunity for comparative studies of mammalian epimorphic regeneration. Transection through the P2 element results in the frequent outcome of fibrotic scar tissue formation. Transection through the more distal P3 element instead results in the regeneration of missing tissue. (credit: Lina M. Quijano et al./Tissue Engineering Part B)

Some of those steps are suggested by what’s possible in mice, where the digit tip has been found capable of regrowing multiple structures, including bone, after amputation.

What about humans?

The highly ambitious goal of epimorphic regeneration for humans would require the regrowth of multiple tissues that have been assembled in the proper conformation and patterns to create a fully functional limb, according to the authors.

Epimorphic regeneration has been observed in distal finger tips of children and young adults. Converting such random events into designed clinical outcomes will require altering the default postamputation progression. It may include the transplantation of cells, scaffolds, and/or soluble factors, as well as controlling microenvironmental aspects, such as oxygen concentration, tissue hydration, mechanical, and electrical cues. (credit: Lina M. Quijano et al./Tissue Engineering Part B)

They note that “it may be possible to suture an engineered epithelial layer, much like the present skin grafts, across the injury site. In-depth understanding of the proper soluble factor communication necessary, however, could lead to a more direct approach of delivering growth factors to the region, leveraging drug delivery paradigms that create spatiotemporal gradients.These interventions are intended to mimic the signals that induce a stable cell mass that functions as a blastema [a mass of cells capable of growth and regeneration into organs or body parts].

“Initial studies in mice have already shown the promise of introducing solubilized [extra-cellular matrices, bone morphogenetic proteins,and matrix metalloproteinases, generated by immune cells] in promoting recruitment/mobilization of endogenous cells to proliferate at the transected bone front. Furthermore, the injury response may also be influenced with external bioreactors … that can control parameters, such as hydration, pH, oxygen concentration, and electrical stimulation.”

The research was supported by the National Institutes of Health and the Fulbright Scholars Program.

Abstract of Looking Ahead to Engineering Epimorphic Regeneration of a Human Digit or Limb

Approximately 2 million people have had limb amputations in the United States due to disease or injury, with more than 185,000 new amputations every year. The ability to promote epimorphic regeneration, or the regrowth of a biologically based digit or limb, would radically change the prognosis for amputees. This ambitious goal includes the regrowth of a large number of tissues that need to be properly assembled and patterned to create a fully functional structure. We have yet to even identify, let alone address, all the obstacles along the extended progression that limit epimorphic regeneration in humans. This review aims to present introductory fundamentals in epimorphic regeneration to facilitate design and conduct of research from a tissue engineering and regenerative medicine perspective. We describe the clinical scenario of human digit healing, featuring published reports of regenerative potential. We then broadly delineate the processes of epimorphic regeneration in nonmammalian systems and describe a few mammalian regeneration models. We give particular focus to the murine digit tip, which allows for comparative studies of regeneration-competent and regeneration-incompetent outcomes in the same animal. Finally, we describe a few forward-thinking opportunities for promoting epimorphic regeneration in humans.