Reindeer antler velvet as a model system of tissue regeneration

低等脊椎动物，如蝾螈，具有显著的组织再生能力，在某种程度上，它们可以在截肢后重新长出整个肢体。然而，随着哺乳动物的进化，这种再生能力已经大大减弱。如何恢复再生是一个很大的兴趣。 鹿角是唯一能够完全再生的哺乳动物器官。卡尔加里大学为教学和研究保留了一个圈养驯鹿资源群，从而为研究组织再生提供了一个独特的（哺乳动物）模型。 在一系列的初步实验中，我的实验室发现，成年鹿角的皮肤（称为“天鹅绒”）能够完全再生而不会形成疤痕，这种现象只在哺乳动物胚胎的皮肤中有过记载。再生的天鹅绒包含新形成的毛囊和相关的皮脂腺，密集的神经支配和重新建立的色素沉着。因此，驯鹿鹿茸为研究成年哺乳动物组织生长和损伤诱导再生的基本细胞和分子动力学提供了一个强大的模型系统。该项目的目标是： 1)确定在鹿茸再生和无疤痕伤口愈合过程中唯一改变的基因。我们将对鹿角绒与鹿角背皮（不能再生）进行高通量基因表达分析。 2)确定已鉴定基因的功能贡献。我们将从遗传学上删除一部分基因，以了解它们在鹿茸生长和/或损伤诱导再生过程中的重要性。 3)确定当地“鹿茸”环境对再生能力的影响。我们的工作表明，天鹅绒在受伤后表现出完全的再生，而同一动物背部皮肤上的类似伤口形成纤维化的“疤痕”，没有附属物或色素。我们将鹿茸移植到背部（非再生部位），然后询问鹿茸是否保留其固有的再生能力。 4)以确定鹿角的细胞起源。在前期工作中，我们从早期鹿茸中分离出一种间充质细胞，该细胞在体外具有持续的自我更新能力，并具有与称为神经嵴的多能胚胎群体相关的特异性标记。我们将分离、鉴定标记的祖细胞，随后将其移植回再生的鹿茸中，然后分析它们在成熟鹿茸中的命运，以了解鹿茸再生的细胞基础。 我们的长期目标是产生有关细胞如何定向形成组织，细胞生长/增殖如何控制以及为什么大多数成年哺乳动物组织再生失败的基本知识。从这项研究计划中收集的知识可能会为未来的工作提供信息，以改善人类和兽医学的伤口愈合。

Lower vertebrates such as salamanders are capable remarkable tissue regeneration, to the extent that they can regrow entire limbs following amputation. However, as mammals have evolved, this regenerative capacity has been largely diminished. How regeneration might be restored is of great interest. Deer antlers are the only mammalian organs capable of complete regeneration. The University of Calgary maintains a resource herd of captive reindeer for teaching and research thus providing a unique (mammalian) model to study tissue regeneration. In a series of preliminary experiments my lab discovered that the adult antler skin (called ‘velvet’) is capable of complete regeneration without forming a scar, a phenomenon only ever documented in embryonic mammalian skin. Regenerated velvet contains newly formed hair follicles and associated sebaceous glands, dense innervation and re-established pigmentation. Thus, the reindeer antler provides a powerful model system to study the basic cellular and molecular dynamics that underlie adult mammalian tissue growth and injury-induced regeneration. The objectives of this project are: 1) To identify genes that are exclusively altered during antler velvet regeneration and during scar-less wound healing. We will perform high-throughput gene expression analyses in antler velvet versus backskin (which does not regenerate). 2) To determine the functional contribution of identified genes. We will genetically delete a subset of genes to understand their importance during antler growth and/or during injury-induced regeneration. 3) To determine the influence of the local ‘antler’ environment on regenerative competence. Our work has shown that the velvet exhibits complete regeneration after injury, whilst similar wounds on backskin in the same animal form fibrotic ‘scar’, devoid of appendages or pigment. We will graft antler velvet on to the back (a non-regenerative site) and then ask whether the velvet retains its inherent regenerative capacity. 4) To determine the cellular origin of antlers. In preliminary work, we isolated a mesenchymal cell from early antler that exhibits continuous self-renewal in vitro and exhibits specific markers associated with a multipotent embryonic population called neural crest. We will isolate, characterize and subsequently transplant labeled progenitors back into the regenerating antler and then analyze their fate within the mature antler in order to understand the cellular basis for antler regeneration. Our long-term goal is to generate fundamental knowledge about how cells are directed to form organized tissues, how cell growth/proliferation is controlled and why regeneration fails in most adult mammalian tissues. Knowledge gleaned from this research program may inform future work to improve wound healing in human and veterinary medicine.