Drug-Induced Regeneration and Re-Innervation in a Mouse Digit Amputation Model
Abstract
This project addresses the Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Area of Tissue Regeneration with a specific focus on the development of novel therapies to repair neurosensory damage, including restoration of the distal end organ sensory interface, as well as preserving the neuromuscular junction after motor nerve injury. In 2005, 1.6 million Americans lived with the loss of a limb, most commonly as a result of vascular disease and/or trauma. That number is expected to more than double by 2050.[1] The only existing therapies are modern prostheses, which only partially restore motor function and have no ability to restore sensory function (touch, hot/cold sensation, etc.), or transplantation, which has numerous limitations and associated risks. In the battlefield, explosive devices frequently result in limb damage or loss among Service members and impair their ability to perform effectively in combat and later in civilian life. Whether due to nerve injuries that reduce function and sensation or due to complete limb loss, these injuries are often debilitating. Therefore, the ability to restore limb components would be an enormous benefit both to military Service members as well as civilians, allowing them to regain function and overcome the trauma and stigma associated with their injuries. Unlike humans, amphibians such as newts and salamanders can fully regrow limbs and digits using stem cells, a special type of cell that has the remarkable potential to develop into many different cell types in the body not only during early life, but also after an injury. While scientists still do not completely understand how these animals regenerate limbs, we think that their immune system plays an important part. Another difference between amphibians and mammals is that amphibians retain the expression of certain genes that can direct limb regeneration.[2] Our laboratory made the surprising discovery that, much like amphibians, a certain strain of laboratory mice called MRL can spontaneously regenerate lost tissue, including skin, hair follicles, and cartilage. When we followed various clues about what makes MRL mice unique, we found that a protein called HIF-1alpha is a likely central actor in this remarkable tissue regeneration. When we turned down HIF-1alpha levels in MRL mice, tissue regeneration no longer occurred. On the other hand, when we treated non-MRL mice (which normally cannot regenerate lost tissue) with a drug we created called 1,4-DPCA nanogel that mimics the MRL HIF-1alpha response, we were able to get these mice to regenerate tissue. When humans lose part of their fingers or toes, there is, in fact, a small amount of tissue that can regrow. Therefore, we believe that we may be able to use 1,4-DPCA nanogel to act like HIF-1alpha in humans with recent digit loss, and achieve regeneration of tissue. Additionally, when nerves further up the limb are injured, they often have very poor recovery due to scarring and delayed healing. This project will test different dosages and injection sites for the so-called “nanomaterial” drug, with the goal of identifying the best way to treat humans with major nerve or amputation injuries. The knowledge we will gain from this research will be an important step in advancing our scientific understanding of how HIF-1alpha works and progress toward discovering future treatments able to heal, and eventually regenerate, entire limbs. [1] Ziegler-Graham K, MacKenzie EJ, Ephraim PL, Travison TG, Brookmeyer R. Estimating the prevalence of limb loss in the United States: 2005 to 2050. Archives of Physical Medicine and Rehabilitation. 2008; 89(3): 422-9. https://www.ncbi.nlm.nih.gov/pubmed/18295618. Accessed on September 1, 2018. [2] Choi Y, Meng F, Cox CS, Lally KP, Huard J, Li Y. Regeneration and Regrowth Potentials of Digit Tips in Amphibians and Mammals. International Journal of Cell Biology. 2017; 2017(5312951). http://doi.org/10.1155/2017
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910467
Entities
People
- Ellen Heber-Katz
Organizations
- Lankenau Institute for Medical Research
- United States Army