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Understanding Stem Cell Therapy
23 Jun at 4:20 pm
Navigating the realms of swords in the rivers and lakes requires heeding diverse opinions. In the quest for knowledge, one must cultivate a serene focus to advance further. Only through profound self-awareness and an understanding of the adversary can one emerge unbeatable in countless battles.
In essence, stem cells are primitive cells endowed with the remarkable ability to self-renew and differentiate into various tissue cell types. They function as the architects of the body. In times of damage, inflammation, or shifts in homeostasis within other cells, tissues, or organs, stem cells may transform into precursor cells for blood, bone, skin, muscle, and more, subsequently differentiating into the required cell types.
It is indeed fascinating that stem cells evoke a sense of myth, often manifesting in isolated success stories that garner acclaim from both the industry and various media outlets. However, given the numerous uncertainties surrounding stem cell therapy, a judicious and rational approach is essential.
A Pragmatic Perspective on Stem Cell Therapy: Paving the Way Forward
Overview:
Currently, the global engagement in stem cell research and development involves hundreds of thousands of individuals, surpassing the monumental scales of the “Manhattan Atomic Energy Project,” “Apollo Moon Landing Project,” and “Human Genome Project” combined. Stem cell therapy has emerged as a beacon of hope for patients who have found traditional medical approaches to be inadequate. The stem cell industry stands poised for action, proclaiming, “desperate patients can’t wait!” It appears that the “opportunity window” for the clinical application of stem cells has opened, and stem cells are narrating a captivating tale—a beautiful myth.
In reality, the present state of stem cell therapy can be succinctly described as “nascent technology with uncertain efficacy.” While some patients experience seemingly “remarkable” effects from stem cell therapy, a larger cohort observes “no effect,” creating a dichotomy akin to “two heavens of ice and fire.”
The Need for a Rational Understanding of Stem Cell Therapy:
Frequently, patients pose questions such as, “What is the effectiveness of stem cells?” and “Are there any side effects of stem cell therapy?” Much like predicting prognosis through the sensitivity of antibiotics or assessing the responsiveness of tumors to chemotherapy drugs, a rational understanding of stem cell therapy is crucial. In clinical terms, if the serum concentration of a drug is too low, therapeutic benefits may not manifest, while excessive concentrations can lead to unacceptable toxicity. A reasonable therapeutic range, often referred to as the “drug therapeutic window,” is defined between these two concentrations.
Similarly, is there a clinical “therapeutic window” to optimize the intervention efficacy of stem cell transplantation? Here are key considerations:
- Definition
- Source
- Uncertain quality due to prolonged in vitro processes
- Unclear mechanism of action
- Ambiguous fate in vivo post-transplantation
- Uncertain validity
- Lack of a risk control plan
- Uncertain consequences of long-term implantation
The current state of stem cell therapy faces critical challenges, hindering the unlocking of its “opportunity window” on a global scale
Numerous laboratories worldwide publish research findings in the expansive field of stem cells. However, many results, even those featured in top journals, prove challenging to replicate. Stem cells, as the primary focus of research, significantly impact the interpretability of these findings. Noteworthy factors influencing judgment include:
- The intricate and challenging tracing of the genetic background of stem cell donors.
- Plausible variations in the biological properties of stem cells derived from different tissue sources.
- The lack of clear definitions for different types of stem cells, leading to potential transformations between them.
- Inconsistency in stem cells as dynamic living organisms.
- Considerations for the selection of stem cell types (tissue sources) for clinical applications.
Anticipating the Global Development of New Stem Cell Therapies
Exploring the clinical applications of stem cells is akin to opening a Pandora’s box. The uncertain nature, whether a blessing or a curse, sparks curiosity, reverie, and expectations, suggesting the arrival of the “spring of stem cell therapy.”
Currently, drug regulatory authorities in countries like the United States, the United Kingdom, France, South Korea, and India have approved over 20 stem cell products to enter various phases of clinical research. Key milestones include:
- On May 4, 2010, the US FDA authorized Prochymal, a human bone marrow mesenchymal stem cell, as an orphan drug for clinically treating type 1 diabetes.
- South Korea approved the world’s first stem cell drug, autologous bone marrow mesenchyme, known as Hearticellgram-AMI, on July 1, 2011, for treating myocardial infarction and heart failure.
- On November 10, 2011, the US FDA approved HEMACORD, an umbilical cord blood hematopoietic progenitor cell, for allogeneic hematopoietic stem cell transplantation, marking the first FDA-approved stem cell product.
- On January 19, 2012, South Korea approved CartiStem, the world’s first allogeneic stem cell drug derived from umbilical cord blood, for the treatment of articular cartilage defects.
Stem Cell Research Nears a Pivotal Scientific and Technological Breakthrough
The regulatory landscape in our country lags significantly behind in addressing the imminent breakthrough in stem cell research, acting as a hindrance to unlocking the “window of opportunity” for the stem cell industry. This delay not only hampers progress but also threatens to lead to further complications and potential regression.
Embarking on the clinical application of stem cells is akin to placing a group of mice in a black box. Once stem cells are implanted in the body, the mystery unfolds, leaving researchers in the dark about their destination and activities. The process involves discreetly observing relevant reactions in the body while contending with the unpredictable “placebo effect.” This “black box” journey delves into the core of life, challenging fundamental ideologies of traditional medical technology and drug development.
On one front, stem cells undergo meticulous screening, observation, manipulation, simulation, and control before being implanted into the recipient. This meticulous approach aims to overcome the technical bottlenecks hindering the opening of the “opportunity window” for stem cell therapy.
Where Mesenchymal Stem Cells Travel Post-Infusion: Distribution and Metabolism
Numerous clinical studies and trials have demonstrated the potential of MSCs in treating various diseases, particularly those deemed challenging. However, the efficacy varies, and instances of unsuccessful treatment are not uncommon. Faced with the accumulation of unsuccessful clinical cases, researchers have embarked on a reflective analysis, seeking to understand why MSCs, known for their therapeutic capabilities, sometimes fall short in clinical applications. Different researchers offer diverse perspectives on this issue.
This article delves into the distribution and metabolism of mesenchymal stem cells once they are infused into the body. It is crucial to recognize the stark differences between MSCs and chemical drugs, including but not limited to:
- Chemical drugs are lifeless, while MSCs are living entities.
- Chemical drugs possess a clear half-life, a trait yet to be identified in MSCs.
- Chemical drugs target specific sites, whereas MSCs exert their effects through multiple channels.
- Chemical drugs undergo passive transportation in the body, while MSCs exhibit active chemotaxis migration.
- Chemical drugs exhibit high uniformity, whereas MSCs display poor homogeneity, and their cell cycle pace is inconsistent. These distinctions prompt contemplation on whether researchers should approach cell treatment with a mindset shaped by chemical drug practices in clinical research or application.
Abundant experimental data confirm that mesenchymal stem cells do not linger in the body for extended periods post-infusion; instead, they are gradually eliminated by the body over time. This elucidates that the mechanism of action of mesenchymal stem cells does not involve differentiation into tissue-specific mature cells. Animal experiments reveal that a robust immune system expedites the clearance of MSCs in vivo, whereas immune-deficient bodies eliminate MSCs at a slower pace. The manner of MSC input also significantly influences their residence time in vivo, with local tissue injection, peripheral intravenous injection, and arterial injection each exerting distinct impacts. Further details will be explored in the following sections.
Cell Reprogramming: The Fascinating Twist in Cellular Transformation
The human body comprises numerous cells, each acquiring specificity during development to perform precise functions within various organs—these specialized cells are known as differentiated cells. Conventionally, it was believed that somatic cells remain differentiated throughout their lifespan, steadfast in their assigned functions. However, a remarkable phenomenon challenges this notion: the process of cellular reprogramming.
On the tree of cell differentiation, there exist trunks (stem cells), main branches (progenitor cells), and small branches (various functional cells). Cellular reprogramming involves altering the fate of cells, and there are two distinct pathways: the first involves retracing from the small branches back to the trunk and then ascending to other small branches, known as induced pluripotent stem cell (iPS) technology. The second pathway comprises a direct leap to another main branch, constituting an indirect lineage conversion technique. In comparison to the route of returning to the trunk, taking this shortcut not only saves time but also reduces the risk of unintended outcomes.
In simpler terms, cellular reprogramming is the process wherein a terminally differentiated cell undergoes a series of changes. If it regresses to the stem cell state, it’s termed iPS. Should it revert to an intermediate transitional cell stage, like progenitor cells, this is labeled lineage switching. Alternatively, if it directly transforms into another terminally differentiated cell, the process is termed transdifferentiation.
Survival Duration of Infused Stem Cells in the Body: Unraveling a Crucial Aspect
Within the industry, the consensus is that stem cell transplantation involves infusing hematopoietic stem cells following myeloablative or semimyeloablative chemotherapy, while stem cell therapy encompasses cell infusion without prior treatment. Myeloablation creates a niche for stem cells, but the fate of directly infused cells, even of autologous origin, remains a pivotal question—can they survive?
Even in myeloablative stem cell infusion, achieving smooth implantation is challenging. While hematopoietic stem cell transplantation is often viewed as a life-saving intervention for patients with refractory and drug-resistant leukemia, the mortality associated with it is substantial, reaching up to 40%. Despite achieving hematopoietic stem cell transplantation with a 6 HLA loci match, 100% successful implantation remains elusive.
Moreover, contemporary stem cell therapy practices forego matching, omitting blood type and sex considerations. Detection focuses solely on pathogenic microorganisms before direct reinfusion. Highly efficient technologies in the industry, such as using mesenchymal stem cells for liver cirrhosis or hematopoietic stem cells/mesenchymal stem cells for diabetic foot treatment, are gaining recognition. The critical question remains: How long do the infused cells persist within the body?
This inquiry delves into a profound subject, directly influencing the choices made by stem cell practitioners regarding treatment options, prediction of therapeutic outcomes, side-effect prevention, and future research endeavors.
Cell Therapy: Paving the Path Forward for Type 1 Diabetes Treatment
In the landscape of type 1 diabetes, the body’s immune system wages an unrelenting war on pancreatic beta cells—specifically, the insulin-producing cells nestled in the Langerhans region of the pancreas—incorrectly identifying them as foreign invaders. As a consequence, these islet β cells lose their ability to produce insulin entirely, resulting in an absolute insulin deficiency within the body and the sustained elevation of blood sugar levels, signaling the onset of diabetes.
Immune-mediated injury to islet β cells serves as the central pathogenic factor in type 1 diabetes, propelling cell therapy focused on enhancing islet function to the forefront of global research. In 2003, the University of Sao Paulo in Brazil pioneered clinical research on treating diabetes through non-myeloablative autologous hematopoietic stem cell transplantation. Subsequently, multinational institutions in Poland, Harvard University, and others made significant strides in this field. Currently, international research endeavors center around the differentiation of stem cells into human islet cells, led primarily by Melton in the United States (Cell, 2014) and the Kiffer team in Canada (Nature Biotechnology, 2014). Stemming from substantial investments, the research landscape continues to evolve, addressing challenges such as a lack of standardization and an unstable therapeutic effect, thereby fostering a more widespread clinical application.
As of today, there are 181 registered stem cell-related clinical trials on ClinicalTrials.gov, with 45 in East Asia.
Current clinical approaches to managing diabetes encompass diet control, metformin, and insulin. Diabetes poses three main challenges: 1) vascular damage; 2) pancreatic islet damage; 3) blood sugar fluctuations, with insulin providing limited control over blood sugar levels. Stem cells emerge as the most promising avenue to address all three diabetes challenges simultaneously.
Hence, cell therapy emerges as the ultimate solution for the prevention and treatment of type 1 diabetes globally. Stem cell and islet transplantation strategically target immune intervention and islet function recovery, aiming to reshape physiological insulin secretion in the body and kindle renewed optimism for type 1 diabetes treatment on a global scale.
