Cell Transplantation Targeting Pain

Neuronal progenitor cells from Dr. Sagen's lab

(March, 2023) Altered sensation sits at the top of shifted perceptual experience following paralysis, and the presence of post-paralysis pain has the potential to consume those affected. Accordingly, The Miami Project has been long pointed at this problem, with a stack of research approaches including application of technology usually not associated with pain management.

Now modern techniques are allowing for revitalization of past accomplishments that abutted biological limits. Cell transplantation offers the potential for a onetime intervention to develop into a wide and lasting effect. Broadly, transplanted cell therapies work when the new cells develop, divide, and/or actively manufacture and export of molecular cargo.

Different approaches—including the use of different cells and different transplantation sites—have been used to target different outcomes, most emblematically targeting the restoration of voluntary movement. However, The Miami Project faculty Dr. Jacqueline Sagen, Ph.D., has been exploring cell transplantation for reducing neuropathic pain since the 1980s.

Now, modern techniques show the potential to overcome what have been the cell’s rate limiters, and combination strategies might maximize their effect. Dr. Sagen’s initial insights began with identifying a specific type of cell, paired with a transplant site that complimented the cell’s characteristics. Chromaffin cells naturally reside in the adrenal glands, atop the kidneys, where they carry out various functions. Of their roles, they are secretors; waiting for signals generated by the brain sent through the autonomic nervous system to secrete a class of molecules called catecholamines (including adrenaline, also known as epinephrine).

As such, they are functionally cellular pumps, producing catecholamines within and then exporting the molecules into their immediate environment. Normally, chromaffin cells in the adrenal glands serve an endocrine function, releasing catecholamines into the blood stream for non-targeted systemic distribution. It just so happens that catecholamines in the spine have been shown to inhibit pain, but usually a selective vascular filter surrounding the brain and spine limit entry of adrenal catecholamines into the spinal cord. One solution could be opening the door to circulating molecules, but this comes with a host of externalities and unintended consequences. What if instead the cellular pumps could be brought in, doing their business locally where their work might have the greatest potential to impact pain?

Transplantation of chromaffin cells, and other synergistic cell types such as neural progenitor cells, was previously achieved, with transplants being well tolerated. However, two rate limiting problems were immediately evident. First, cells were derived from the adrenal glands of human organ donors and could not be made to reproduce after donation. This meant that each cell transplant required a donor, greatly limiting the number of transplants that could be performed and hindering the feasibility of scaling.

Furthermore, there were logistical considerations for cell treatment so that the recipient’s immune system did not reject the transplant. Induced pluripotent stem cells allow for certain, common types of developed cells to be walked back through their differentiated development to a type of progenitor cell—a pluripotent stem cell—that has the potential to become many other kinds of cells. That cell can then be coerced to differentiate into a target cell type different than the cell type that the stem cell was derived from, such as a chromaffin cell. Inducing these desired cells from cells that are naturally in abundance overcomes the problem of insufficient cell numbers.

Furthermore, if the original cell type used to derive the stem cell is taken from the same person that will receive the induced transplant, immune rejection is much less likely. Thus, these induced autologous (derived from the recipient) cells overcome the two biological rate limiters that previously gave pause to certain cell transplant approaches targeting neuropathic pain.

Now, Dr. Sagen’s team has preliminarily demonstrated the ability to utilize induced pluripotent stem cells from adult human cell types that are abundant and obtained with minimal donor burden (blood and skin), bypassing ethical constraints regarding the use of embryonic germ cells which were once considered the only source of pluripotent stem cells. The induced cells were then differentiated into chromaffin-like cells, or co-cultured with their common neural progenitor cell colleagues.

Preliminary results indicate that chromaffin cells derived from human induced pluripotent stem cells produce sustained alleviation of chronic pain symptoms in preclinical chronic pain models including that following spinal cord injury. This was achieved using a relatively noninvasive intrathecal cell injection, similar to a spinal tap procedure. Further, the use of these cell sources may be tailored for pain type, location, and severity using analgesic gene enhancement, matrix embedding, or co-transplantation with complementary cells.

Included in Dr. Sagen’s team on this project was Lauren Tierney, an undergraduate student in the Steinbrenner Scholars Program, a 10 week funded, merit based, research driven summer internship. The application of emerging technology to realize latent insights combined with the training of the future generation of neuroscientists surely gives reason for hope.

Experiments are also ongoing to test the combined effect of cell transplant plus therapeutic adjuvants, such as exercise which has been shown to reduce inflammation within the spinal cord. By creating supportive environments for cell transplants, these conjunctive therapies might unlock or optimize the potential of the transplanted cells.